Pyrazine derivatives useful as adenosine receptor antagonists

ABSTRACT

The present invention provides a compound of formula (I) wherein: A represents an optionally substituted monocyclic or polycyclic aryl or heteroaryl group B represents an optionally substituted monocyclic nitrogen-containing heteroaryl group; and either a) R 1  and R 2  represent hydrogen or specified substituents, or b) R 2 , R 1  and the —NH— group to which R 1  is attached, form a moiety selected from the moiety of formulae (IIa) and (IIb): (IIa) These compounds are useful as antagonists of the A2B receptor, for instance in the treatment of asthma.

The present invention relates to new antagonists of the A_(2B) adenosinereceptor. These compounds are useful in the treatment, prevention orsuppression of diseases and disorders known to be susceptible toimprovement by antagonism of the A_(2B) adenosine receptor, such asasthma, chronic obstructive pulmonary disorder, pulmonary fibrosis,emphysema, allergic diseases, inflammation, reperfusion injury,myocardial ischemia, atherosclerosis, hypertension, retinopathy,diabetes mellitus, inflammatory gastrointestinal tract disorders, and/orautoimmune diseases.

Adenosine regulates several physiological functions through specificcell membrane receptors, which are members of the G-protein coupledreceptor family. Four distinct adenosine receptors have been identifiedand classified: A₁, A_(2A), A_(2B) and A₃.

The A_(2B) adenosine receptor subtype (see Feoktistov, I., Biaggioni, I.Pharmacol. Rev. 1997, 49, 381-402) has been identified in a variety ofhuman and murine tissues and is involved in the regulation of vasculartone, smooth muscle growth, angiogenesis, hepatic glucose production,bowel movement, intestinal secretion, and mast cell degranulation.

In view of the physiological effects mediated by adenosine receptoractivation, several A_(2B) receptor antagonists have been recentlydisclosed for the treatment or prevention of, asthma,bronchoconstriction, allergic diseases, hypertension, atherosclerosis,reperfusion injury, myocardial ischemia, retinopathy, inflammation,gastrointestinal tract disorders, cell proliferation diseases and/ordiabetes mellitus. See for example WO03/063800, WO03/042214, WO03/035639, WO02/42298, EP 1283056, WO 01/16134, WO 01/02400, WO01/60350or WO 00/73307.

It has now been found that certain pyrazine derivatives are novel potentantagonists of the A_(2B) adenosine receptor and can therefore be usedin the treatment or prevention of these diseases.

Further objectives of the present invention are to provide a method forpreparing said compounds; pharmaceutical compositions comprising aneffective amount of said compounds; the use of the compounds in themanufacture of a medicament for the treatment of pathological conditionsor diseases susceptible to improvement by antagonism of the A_(2B)adenosine receptor; and methods of treatment of pathological conditionsor diseases susceptible to amelioration by antagonism of the A_(2B)adenosine receptor comprising the administration of the compounds of theinvention to a subject in need of treatment.

Thus, the present invention is directed to new pyrazine derivatives offormula (I)

wherein:A represents a monocyclic or polycyclic aryl or heteroaryl groupoptionally substituted by one or more substituents independentlyselected from the group comprising halogen atoms, C₁₋₄alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, C₁₋₄alkoxy, aryl-C₁₋₄alkoxy,C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl, hydroxy andcyano groups;B represents a monocyclic nitrogen-containing heteroaryl groupoptionally substituted by one or more substituents independentlyselected from the group comprising halogen atoms, C₁₋₄alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl, C₁₋₄alkylthio, mono ordi-C₁₋₄alkylamino, trifluoromethyl and cyano groups;and either

-   -   a) R¹ represents a group of formula:

-L-(CR′R″)_(n)-G

-   -   -   wherein L represents a linking group selected from the group            consisting of direct bond, —(CO)—, —(CO)O—, —(CO)NR′—, —SO₂—            and —SO₂NR′—;        -   R′ and R″ are independently selected from the groups            consisting of hydrogen atoms and C₁₋₄alkyl groups        -   n is an integer from 0 to 6; and        -   G is selected from the group consisting of hydrogen atom and            C₁₋₄alkyl, aryl, heteroaryl, C₃₋₈cycloalkyl and saturated or            unsaturated heterocyclic groups, wherein the alkyl,            C₃₋₈cycloalkyl, aryl or heteroaryl groups are unsubstituted            or substituted with one or more substituents selected from            halogen atoms, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, mono or            di-C₁₋₄alkylamino, trifluoromethyl, trifluoromethoxy,            carbamoyl, carboxy and cyano groups;        -   and R² represents a group selected from hydrogen atoms,            halogen atoms and C₁₋₄alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl,            C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino,            C₁₋₄alkoxy-(CO)—, —NH₂, mono or di-C₁₋₄alkylamino-(CO)— and            cyano groups wherein the alkyl, alkenyl and alkynyl groups            may be unsubstituted or substituted by one aryl or            heteroaryl group            or

    -   b) R², R¹ and the —NH— group to which R¹ is attached, form a        moiety selected from the moiety of formulae (IIa) and (IIb):

-   -   wherein:    -   R^(a) is selected from hydrogen atom, halogen atoms, —OH, —NH₂        or groups selected from C₁₋₄alkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl,        heteroaryl-C₁₋₄alkyl, saturated heterocyclic rings, C₁₋₄alkoxy        and C₁₋₄alkylthio; wherein the aryl or heteroaryl moieties are        unsubstituted or substituted with one or more groups selected        from halogen atoms, C₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxy, mono        or di-C₁₋₄alkylamino, cyano, trifluoromethyl, trifluoromethoxy,        carbamoyl and carboxy;    -   R^(b) is selected from hydrogen, halogen atoms and groups        selected from C₁₋₄alkyl, C₁₋₄alkylamino, arylC₁₋₄alkylamino and        —NH₂;

and the pharmaceutically acceptable salts and N-oxides thereof; with theproviso that the compound is not selected fromN-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide,N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamideandN-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide.

As used herein the terms alkyl or lower alkyl embraces optionallysubstituted, linear or branched hydrocarbon radicals having 1 to 8,preferably 1 to 6 and more preferably 1 to 4 carbon atoms. Preferredsubstituents on the alkyl groups are halogen atoms and hydroxy groups.

Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyland tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl,1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl,1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl,3-methylpentyl and iso-hexyl radicals.

As used herein the term alkynyl embraces optionally substituted, linearor branched radicals having 2 to 8, preferably 2 to 6 and morepreferably 2 to 4 carbon atoms which contain 1 or 2, preferably 1 triplebond. The alkynyl groups are preferably unsubstituted or substituted byhalogen atoms.

Examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl,butyn-2-yl, butyn-3-yl and 1-methyl-propyn-2-yl.

As used herein, the term cycloalkyl embraces saturated carbocyclicradicals and, unless otherwise specified, a cycloalkyl radical typicallyhas from 3 to 7 carbon atoms.

Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. When a cycloalkyl radical carries 2 or more substituents,the substituents may be the same or different. Preferred substituents onthe cycloalkyl groups are halogen atoms and hydroxy groups.

As used herein, unless otherwise provided, the term aryl radicalembraces typically a C₅-C₁₄ monocyclic or polycyclic aryl radical suchas phenyl or naphthyl, anthranyl or phenanthryl. Optionally substitutedphenyl is preferred. When an aryl radical carries 2 or moresubstituents, the substituents may be the same or different. Preferredsubstituents on the aryl radicals are halogen atoms and groups selectedfrom —OR³, —SR³, —R³, and —NHR³. Halogen atoms are particularlypreferred.

As used herein, unless otherwise provided, the term heteroaryl radicalembraces typically a 5- to 14-membered ring system comprising at leastone heteroaromatic ring and containing at least one heteroatom selectedfrom O, S and N. A heteroaryl radical may be a single ring or two ormore fused rings wherein at least one ring contains a heteroatom.

Examples of monocyclic heteroaryl radicals include pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, oxazolyl, imidazolyl,thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, triazolyl,imidazolidinyl and pyrazolyl radicals. Pyridyl, thienyl, furyl,pyridazinyl and pyrimidinyl radicals are preferred.

When a heteroaryl radical carries 2 or more substituents, thesubstituents may be the same or different. Preferred substituents on theheteroaryl radicals are halogen atoms and groups selected from —OR³,—SR³, —R³, and —NHR³.

As used herein, the term heterocyclic group embraces typically anheteroaromatic or non-aromatic, saturated or unsaturated C₃-C₁₀carbocyclic ring, such as a 5, 6 or 7 membered radical, in which one ormore, for example 1, 2, 3 or 4 of the carbon atoms, preferably for 2, ofthe carbon atoms are replaced by a heteroatom selected from N, O and S.Non-saturated heterocyclyl radicals are preferred. A heterocyclicradical may be a single ring or two or more fused rings wherein at leastone ring contains a heteroatom. When a heterocyclyl radical carries 2 ormore substituents, the substituents may be the same or different.

Examples of monocyclic, nitrogen-containing heterocyclic radicalsinclude pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl,oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrrolyl, pyridinyl,triazolyl, imidazolidinyl, pyrazolyl, piperidyl, pyrrolidyl, pyrrolinyl,piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl,pirazolidinyl, quinuclidinyl, pyrazolyl, tetrazolyl, imidazolidinyl,imidazolyl, and 3-aza-tetrahydrofuranyl. Pyridyl, pyrimidinyl, pirazinyland pyridazinyl are preferred radicals.

Where a heterocyclyl radical carries 2 or more substituents, thesubstituents may be the same or different. Preferred substituents on thearyl radicals are halogen atoms and group selected from —OR³, —SR³, —R³,and —NHR³. Halogen atoms are particularly preferred.

As used herein, some of the atoms, radicals, moieties, chains or cyclespresent in the general structures of the invention are “optionallysubstituted”. This means that these atoms, radicals, moieties, chains orcycles can be either unsubstituted or substituted in any position by oneor more, for example 1, 2, 3 or 4, substituents, whereby the hydrogenatoms bound to the unsubstituted atoms, radicals, moieties, chains orcycles are replaced by chemically acceptable atoms, radicals, moieties,chains or cycles. When two or more substituents are present, eachsubstituent may be the same or different.

As used herein, the term halogen atom embraces chlorine, fluorine,bromine or iodine atoms typically a fluorine, chlorine or bromine atom,most preferably chlorine or fluorine. The term halo when used as aprefix has the same meaning.

As used herein, the term pharmaceutically acceptable salt embraces saltswith a pharmaceutically acceptable acid or base. Pharmaceuticallyacceptable acids include both inorganic acids, for example hydrochloric,sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitricacid and organic acids, for example citric, fumaric, maleic, malic,mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic,methanesulphonic, ethanesulphonic, benzenesulphonic, cyclohexylsulfamic(cyclamic) or p-toluenesulphonic acid. Pharmaceutically acceptable basesinclude alkali metal (e.g. sodium or potassium) and alkali earth metal(e.g. calcium or magnesium) hydroxides and organic bases, for examplealkyl amines, arylalkyl amines and heterocyclic amines.

Other preferred salts according to the invention are quaternary ammoniumcompounds wherein an equivalent of an anion (X—) is associated with thepositive charge of the N atom. X— may be an anion of various mineralacids such as, for example, chloride, bromide, iodide, sulphate,nitrate, phosphate, or an anion of an organic acid such as, for example,acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate,malate, mandelate, trifluoroacetate, methanesulphonate andp-toluenesulphonate. X— is preferably an anion selected from chloride,bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinateor trifluoroacetate. More preferably X— is chloride, bromide,trifluoroacetate or methanesulphonate.

As used herein, an N-oxide is formed from the tertiary basic amines orimines present in the molecule, using a convenient oxidising agent.

In one embodiment the present invention is also directed to new pyrazinederivatives of formula (I):

wherein:A represents a monocyclic or polycyclic aryl or heteroaryl groupoptionally substituted by one or more substituents independentlyselected from the group comprising halogen atoms, C₁₋₄alkyl,C₃₋₈cycloalkyl, C₁₋₄cycloalkyl-C₁₋₄alkyl, C₁₋₄alkoxy, aryl-C₁₋₄alkoxy,C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl, hydroxy, andcyano groups;B represents a monocyclic nitrogen-containing heteroaryl groupoptionally substituted by one or more substituents independentlyselected from the group comprising halogen atoms, C₁₋₄alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl, C₁₋₄alkylthio, mono ordi-C₁₋₄alkylamino, trifluoromethyl and cyano groups;and either

-   -   a) R¹ represents a group of formula:

-L-(CR′R″)_(n)-G

-   -   -   wherein L represents a linking group selected from the group            consisting of direct bond, —(CO)—, —(CO)O—, —(CO)NR′—, —SO₂—            and —SO₂NR′—;        -   R′ and R″ are independently selected from the groups            consisting of hydrogen atoms and C₁₋₄alkyl groups        -   n is an integer from 0 to 6; and        -   G is selected from the group consisting of hydrogen atom and            C₁₋₄alkyl, aryl, heteroaryl, C₃₋₈cycloalkyl and saturated or            unsaturated heterocyclic groups, wherein the aryl or            heteroaryl groups are unsubstituted or substituted with one            or more substituents selected from halogen atoms, C₁₋₄alkyl,            C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino,            trifluoromethyl and cyano groups;        -   and R² represents a group selected from hydrogen atoms,            halogen atoms and C₁₋₄alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl,            C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino,            C₁₋₄alkoxy-(CO)—, mono or di-C₁₋₄alkylamino-(CO)— and cyano            groups wherein the alkyl, alkenyl and alkynyl groups may be            unsubstituted or substituted by one aryl or heteroaryl group            or

    -   b) R², R¹ and the —NH— group to which R¹ is attached form a        moiety selected from the moiety of formulae (IIa) and (IIb):

-   -   wherein:    -   R^(a) is selected from hydrogen atom, halogen atoms, —OH, —NH₂        or groups selected from C₁₋₄cycloalkyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl,        heteroaryl-C₁₋₄alkyl, saturated heterocyclic rings, C₁₋₄alkoxy        and C₁₋₄alkylthio; wherein the aryl or heteroaryl moieties are        unsubstituted or substituted with one or more groups selected        from halogen atoms, C₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxy, mono        or di-C₁₋₄alkylamino, cyano and trifluoromethyl;    -   R^(b) is selected from hydrogen, halogen atoms and groups        selected from C₁₋₄alkyl, C₁₋₄alkylamino, arylC₁₋₄alkylamino and        —NH₂;

and the pharmaceutically acceptable salts and N-oxides thereof, with theproviso that the compound is not selected fromN-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide,N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamideandN-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide.

In one embodiment of the present invention the group G is selected fromthe group consisting of hydrogen atom and C₁₋₄alkyl, aryl,C₃₋₈cycloalkyl and saturated or unsaturated non-aromatic heterocyclicgroups, wherein the aryl groups are unsubstituted or substituted withone or more substituents selected from halogen atoms, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyland cyano groups;

Preferred compounds of the invention are those wherein A represents anoptionally substituted monocyclic five or six-membered heterocyclic ringor an optionally substituted phenyl ring. More preferably A representsan optionally substituted pyridine, oxazol, furan, pyrazol, pyrazine orphenyl group; still more preferably A represents an optionallysubstituted pyridine, oxazol, furan or pyrazol group. More preferably Arepresents a pyridine ring which is either unsubstituted or substitutedwith alkoxy group or halogen atom, still more preferably A represents apyridine ring which is either unsubstituted or substituted with halogenatom. Yet still preferably A represents a pyridine ring unsubstituted orsubstituted with one or two halogen atoms; more preferably A representsa pyridine ring unsubstituted or substituted with one halogen atom . . ..

In another embodiment of the present invention the group B represents anoptionally substituted monocyclic, five or six-membered heterocyclicring having one or two nitrogen atoms. More preferably B represents anoptionally substituted pyridine or pyrimidine group. Still morepreferably B represents a pyridine ring either unsubstituted orsubstituted with one or two halogen atoms; more preferably B representsa pyridine ring either unsubstituted or substituted with one halogenatom.

In an alternative embodiment of the present invention R¹ represents agroup of formula:

-L-(CR′R″)_(n)-G

-   -   wherein L represents a direct bond or a group —(CO)—,    -   R′ and R″ are independently selected from the groups consisting        of hydrogen atom and methyl groups    -   n is an integer from 0 to 6; and        G is selected from the group consisting of hydrogen atom,        C₁₋₄alkyl, C₃₋₈cycloalkyl, aryl or heteroaryl groups wherein the        C₁₋₄alkyl, C₃₋₈cycloalkyl aryl or heteroaryl groups are        unsubstituted or substituted with one or more substituents        selected from halogen atoms.

In a further alternative embodiment of the present invention G isselected from the group consisting of hydrogen atom, C₁₋₄alkyl,C₃₋₈cycloalkyl, aryl or heteroaryl groups wherein the aryl or heteroarylgroups are unsubstituted or substituted with one or more substituentsselected from halogen atoms.

More preferably R¹ represents a group of formula:

-L-(CR′R″)_(n)-G

-   -   wherein L represents a group —(CO)—,    -   R′ and R″ are independently selected from the groups consisting        of hydrogen atom and methyl groups    -   n is an integer from 0 to 6; and    -   G is selected from the group consisting of hydrogen atom and        C₃₋₈cycloalkyl groups.

Still more preferably R¹ represents a group of formula:

-L-(CR′R″)_(n)-G

-   -   wherein L represents a group —(CO)—,    -   R′ and R″ are independently selected from the groups consisting        of hydrogen atom and methyl groups    -   n is an integer from 0 to 3; and    -   G represents a C₃₋₈cycloalkyl group substituted with one or more        substituents selected from halogen atoms.

In still another embodiment of the present invention R² represents ahydrogen atom.

In still another embodiment of the present invention R², R¹ and the —NH—group to which R¹ is attached form a moiety of formula (IIa) or (IIb):

-   -   wherein:    -   R^(a) is selected from C₃₋₈cycloalkyl, saturated heterocyclic        ring, aryl and heteroaryl groups; wherein the aryl or heteroaryl        moieties are unsubstituted or substituted with one or more        halogen atoms; and    -   R^(b) represents a hydrogen atom.

In still another embodiment of the present invention R², R¹ and the —NH—group to which R¹ is attached form a moeity of formula (IIb):

-   -   wherein:        R^(a) is selected from C₃₋₈cycloalkyl, saturated heterocyclic        ring, aryl and heteroaryl groups; wherein the aryl or heteroaryl        moieties are unsubstituted or substituted with one or more        halogen atoms.

Particular individual compounds of the invention for their use in themanufacture of a medicament for the treatment of a pathologicalcondition or disease susceptible to improvement by antagonism of theA_(2B) adenosine receptor include:

-   6-(3-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine-   5-(3-Chloropyridin-4-yl)-6-(3-fluorophenyl)pyrazin-2-amine-   6-(3-Fluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-amine-   6-(3-Fluorophenyl)-5-(1,3-thiazol-5-yl)pyrazin-2-amine-   6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-amine-   6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-amine-   5-Pyridin-4-yl-6-(2-thienyl)pyrazin-2-amine-   6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-amine-   6-(2-Furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-amine-   5-(2-Cyclopropylpyrimidin-4-yl)-6-(2-furyl)pyrazin-2-amine-   6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-amine-   6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine-   6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine-   5,6-Dipyridin-4-ylpyrazin-2-amine-   N-[6-(5-Methyl-2-furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   6-(2-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine-   N-[6-(3-Fluoropyridin-4-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(3-Chloropyridin-4-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(1,3-Oxazol-5-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(1,3-Oxazol-2-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-2-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2,2-dimethylpropanamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   6-(3-Fluorophenyl)-N-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine-   N-[6-(3-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]pyrimidin-5-amine-   N-[6-(3-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide-   N-[6-(2-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   6-(2-Furyl)-N-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]pyrimidin-5-amine-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]propanamide-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclobutanecarboxamide-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopentanecarboxamide-   N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]-2-methylpropanamide-   2-Cyclopentyl-N-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide-   4-Fluoro-N-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]benzamide-   N-Cyclopentyl-N′-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]urea-   N-{6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-yl}acetamide-   N-{6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-yl}cyclopropanecarboxamide-   N-[5-Pyridin-4-yl-6-(2-thienyl)pyrazin-2-yl]acetamide-   N-[6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-yl]acetamide-   N-[6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(2-Furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(2-Cyclopropylpyrimidin-4-yl)-6-(2-furyl)pyrazin-2-yl]cyclopropanecarboxamide-   N-[6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-yl]acetamide-   N-[6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide-   N-(6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)acetamide-   N-(6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide-   N-Cyclopentyl-N′-(6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)urea-   N-(4-Fluorophenyl)-N′-(6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)urea-   N-(6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide-   N-(6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)cyclobutanecarboxamide-   N-Cyclopentyl-N′-(6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)urea-   N-(4-Fluorophenyl)-N′-(6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)urea-   6-Pyridin-3-yl-5-pyridin-4-yl-N-1,3-thiazol-2-ylpyrazin-2-amine-   N-(5,6-Dipyridin-4-ylpyrazin-2-yl)cyclopropenecarboxamide-   3-Bromo-6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine-   3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine-   3-Bromo-6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine-   3-Amino-5-(2-furyl)-6-pyridin-4-ylpyrazine-2-carbonitrile-   3-Ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine-   6-(2-Furyl)-3-(phenylethynyl)-5-pyridin-4-ylpyrazin-2-amine-   6-(2-Furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-amine-   3-Ethyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine-   N-[3-Cyano-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide-   N-[6-(2-Furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[3-Ethyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide-   5-Phenyl-6-pyridin-4-ylpyrazine-2,3-diamine-   5-(3-Fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine-   3-Amino-5-(3-fluorophenyl)-6-pyridin-4-ylpyrazin-2-ol-   6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   6-(3-Fluorophenyl)-2-methyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one-   6-(3-Fluorophenyl)-5-pyridin-4-yl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazine-   5-(4-Fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine-   5-(3-Methylphenyl)-6-pyridin-4-ylpyrazine-2,3-diamine-   5-(2-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine-   6-(2-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine-   5-(3-Chlorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine-   6-(3-Chlorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine-   6-(3-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine-   5-(2-Furyl)-6-pyridin-4-ylpyrazine-2,3-diamine-   3-Amino-5-(2-furyl)-6-pyridin-4-ylpyrazin-2-ol-   6-(2-Furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   2-Cyclopentyl-6-(2-furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   2,6-Di-2-fury)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   6-(2-Furyl)-2-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   6-(2-Furyl)-2,5-dipyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   6-(2-Furyl)-2-pyridin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   6-(2-Furyl)-2-pyrazin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   5-(5-Methyl-2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine-   5-(1-Benzofuran-2-yl)-6-pyridin-4-ylpyrazine-2,3-diamine-   5-Pyridin-3-yl-6-pyridin-4-ylpyrazine-2,3-diamine-   5-Pyridin-3-yl-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one-   2-(4-Fluorophenyl)-6-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   5-(2-Furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine-   3-Amino-5-(2-furyl)-6-pyrimidin-4-ylpyrazin-2-ol-   6-(2-Furyl)-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine-   5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one-   6-(2-Furyl)-2-pyridin-3-yl-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine-   5-(2-Furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine-   3-Amino-5-(2-furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-ol-   6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine-   5-(3-Methyl-2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine-   5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)pyrazine-2,3-diamine-   5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)-1H-imidazo[4,5-b]pyrazine-   3-(2-Furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine-   3-(2-Furyl)-6-phenyl-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine-   6-Cyclohexyl-3-(2-furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine-   5-(3,5-Difluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine-   N-[6-(6-Hydroxypyridin-3-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   1-Cyclopropyl-3-(6-(pyridin-2-yl)-5-(pyridin-4-yl)pyrazin-2-yl)urea-   N-[5-(3-Fluoropyridin-4-yl)-6-(6-methoxypyridin-3-yl)pyrazin-2-yl]cyclopropane    carboxamide-   N-[5,6-bis(3-Fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-quinolin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-(5-methoxypyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-(6-hydroxypyridin-3-yl)pyrazin-2-yl]cyclopropane    carboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropane    carboxamide-   N-[5-(3-fluoropyridin-4-yl)-6-pyrimidin-5-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[3-(3-fluoropyridin-4-yl)-2,2′-bipyrazin-6-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoro-1-oxidopyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-fluoropyridin-4-yl)-6-(5-fluoropyridin-2-yl)pyrazin-2-yl]cyclopropane-carboxamide-   N-[6-(2-Fluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropane-carboxamide-   N-[6-(2,4-Difluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropane-carboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-(1,3-oxazol-2-yl)pyrazin-2-yl]cyclopropane-carboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]propanamide-   2-Cyclopentyl-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopentanecarboxamide-   3,3,3-Trifluoro-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]propanamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclobutanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide-   2-Cyclopropyl-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2-morpholin-4-ylacetamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2-methylpropanamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]methanesulfonamide-   N-[5-(3,5-Difluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropane    carboxamide-   N-[5-(3,5-Difluoropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropane    carboxamide-   N-[5-(3,5-difluoropyridin-4-yl)-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropane-carboxamide-   N-[5-(3,5-difluoro-1-oxidopyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropane-carboxamide-   N-[6-(3,5-Difluoropyridin-2-yl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide-   6-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-   2-(3-Fluoropyridin-4-yl)-6-pyridin-2-yl-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-   2-(3-Fluoropyridin-4-yl)-3,6-dipyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-   4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitrile-   4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzamide-   2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine-   2-(4-Fluorophenyl)-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-2-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazine-   2-[1-(4-Chlorophenyl)ethyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-2-morpholin-4-yl-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine-   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-N-(2,2,2-trifluoro-1-methylethyl)pyrazin-2-amine-   5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-N-(2,2,2-trifluoroethyl)pyrazin-2-amine

Of outstanding interest are:

-   6-(3-Fluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-amine-   N-[6-(1,3-Oxazol-5-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-2-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Chloropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide-   N-(6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide-   N-(4-Fluorophenyl)-N′-(6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)urea-   N-(6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide-   6-(2-Furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-amine-   5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one-   6-(2-Furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine-   N-[5-(3-Fluoropyridin-4-yl)-6-(6-methoxypyridin-3-yl)pyrazin-2-yl]cyclopropane    carboxamide-   N-[3-(3-fluoropyridin-4-yl)-2,2′-bipyrazin-6-yl]cyclopropanecarboxamide-   N-[5-(3,5-Difluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide-   6-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-   2-(3-Fluoropyridin-4-yl)-3,6-dipyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine

Compounds of general formula (I) and in particular those wherein A, Band R¹ are as hereinabove defined and R² is hydrogen (general formula(Ia)) may be prepared following the synthetic scheme depicted in FIG. 1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 exemplifies a synthetic scheme used for the preparation ofcompounds of general formula (I) wherein R² is hydrogen (general formula1(a)).

FIG. 2 exemplifies a synthetic scheme used for the preparation ofcompounds of general formula (I) wherein R² is hydrogen and B is anoptionally substituted pyrimidine ring (general formula 1(b)).

FIG. 3 exemplifies a synthetic scheme used for the preparation ofcompounds of general formula (I) wherein R² is not hydrogen.

FIG. 4 exemplifies a synthetic scheme used for the preparation ofcompounds of general formula (I) wherein R², R¹, and the —NH— group towhich R¹ is attached form a moiety of formula II(a).

FIG. 5 exemplifies an alternative synthetic scheme used for thepreparation of compounds of general formula (I) wherein R², R¹, and the—NH— group to which R¹ is attached form a moiety of formula II(a).

FIG. 6 exemplifies a synthetic scheme used for the preparation ofcompounds of general formula (I) wherein R¹ represents -L-(CR′R″)n-G-wherein L represents a direct bond.

Treatment of 2-amino-6-chloropyrazine (III) with iodinating agents suchas N-iodosuccinimide or iodine in polar solvents such as DMSO, DMF orwater at a temperature in a range of 0° C. to 80° C. provides compoundsof general formula (IV). Regioselective Suzuki-type coupling of2-amino-6-chloro-5-iodopyrazine (IV) using the boronic acid or boronatederivative of B using a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1:1) in solvents such as toluene or dioxane inthe presence of an aqueous solution of a base such as sodium or cesiumcarbonate and at a temperature between 25° C. to 200° C. providescompounds of general formula (V).

Similarly, Stifle-type cross coupling of 2-amino-6-chloro-5-iodopyrazine(IV) using the organotin derivative of B in the presence of palladiumcatalysts such as tetrakis(triphenylphosphine)palladium (0) in solventssuch as xylene or dimethylformamide at a temperature between 25° C. to200° C. also provides compounds of general formula (V).

Similarly, Negishi-type cross coupling of2-amino-6-chloro-5-iodopyrazine (IV) using the organozinc derivative ofB in the presence of palladium catalysts such as tetrakis(triphenylphosphine)palladium (0) in solvents such as tetrahydrofuran ata temperature between 25° C. to 180° C. also provides compounds ofgeneral formula (V).

A further Suzuki, Stille or Negishi-type coupling of the compounds offormula (V) using the corresponding boronic acid, boronate, organotin ororganozinc derivative of A under the standard procedures for Pdcatalyzed reactions described above provides the 2-aminopyrazines (VI).

In another synthetic pathway, 2-aminopyrazines (VI) can be preparedstarting from 2-amino-6-chloropyrazine (III) by Suzuki, Stille orNegishi-type coupling reactions using the corresponding boronic acid,boronate, organotin or organozinc derivative of A under the standardprocedures for Pd catalyzed reactions described above to yield thecompounds of formula (VII).

Subsequent regioselective bromination or iodination of the compounds offormula (VII) using reagents such as Br₂, I₂ or N-halosuccinimide inpolar aprotic solvents such as DMF and at temperatures ranging from 0°C. to 100° C., yield the compounds of formula (VIII). A further Suzuki,Stille or Negishi-type coupling reaction of the compounds of formula(VIII) using the corresponding boronic acid, organotin or organozincderivative of B under the standard procedures for Pd catalyzed reactionsdescribed above provides the compounds of formula (VI).

Compounds of general formula (Ia) wherein R¹ represents a group offormula -L-(CR′R″)_(n)-G and L represents a linking group selected from—(CO)—, —(CO)O—, —(CO)NR′—, —SO₂— and —(SO₂)NR′— are prepared bytreatment of compounds of formula (VI) with acylating agents such asanhydrides, acid chlorides, acylcarbonates, isocianates, sulfonylchlorides or sulfamoyl chlorides in apolar organic solvents such as THFor pyridine and in the presence of a convenient organic base (such astriethylamine) or inorganic base at a temperature between 25° C. to 100°C., and eventually acylating with carboxylic acids using coupling agentssuch as diethylcarbodiimide.

Similarly, compounds of general formula (IV) and (V) may be convertedinto the compounds of general formula (IX) and (X) respectively usingthe general coupling procedures described above.

Compound of formula (IX) may be converted into compounds of formula (X)using the procedures described above for converting compounds of formula(IV) into compounds of formula (V).

Similarly, compounds of formula (X) may be converted in compounds offormula (Ia) using the procedures described above for convertingcompounds of formula (V) into compounds of formula (VI).

Compounds of general formula (Ia) wherein R¹ represents a group offormula -L-(CR′R″)_(n)-G, L represents a direct bond and G represents anaryl or heteroaryl group may also be prepared by treatment of compoundsof general formula (VI) with the corresponding aryl or heteroarylhalides (preferably bromides, iodides or chlorides) The reaction iscarried out using the palladium and/or copper catalyzed general methodsfor the arylation of amines (for references see Yin, J. et al. Org.Lett. 2002, 4 (20), 3481 and Buchwald S. L. et al. J. Am. Chem. Soc.2002, 124, 7421).

Compounds of general formula (I) and in particular those wherein A andR¹ are as hereinabove defined, R² is hydrogen and B is an optionallysubstituted pyrimidine ring (general formula (Ib)) may be preparedfollowing the synthetic scheme depicted in FIG. 2.

Treatment of halopyrazines of general formula (VIII) wherein Xrepresents a bromine, chlorine or iodine atom under Heck-type couplingconditions using alkylvinyl ether derivatives such as butyl vinyl ether,palladium catalysts such as palladium (II) acetate, phosphine ligandssuch as 1,3-bis(diphenylphosphino)propane (DPPP), naphtalene, insolvents such as dimethylformamide in the presence of an aqueoussolution of a base such as potassium carbonate and at a temperaturebetween 25° C. to 180° C. provides compounds of general formula (XI).Further treatment with N,N-dimethylformamide diethyl acetal at atemperature between 25° C. to 110° C. provides compounds of generalformula (XII).

These products are in turn cyclised to the corresponding pyrimidinederivatives (XIII) by reaction with the corresponding amidines (whenR=C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, trifluoromethyl, aryl orheteroaryl), imidothiocarbamates (when R is C₁₋₄alkylthio) or withguanidines (when R=mono or dialkylamino) in solvents such as ethanol,toluene or mixtures of them at a temperature between 50° C. to 180° C.In general, alkylthiopyrimidines can be converted into diverselysubstituted pyrimidines by nucleophilic displacement of the alkylthiogroup or the corresponding sulfone by a convenient nucleophile such ascyanide, mono or dialkylamine or halide. Compounds of general formula(Ib) are prepared using the general procedures described above for thesynthesis of compounds (Ia) from compounds (VI).

Compounds of general formula (I) and in particular those wherein A, Band R¹ are as hereinabove defined and R² is not hydrogen may be preparedfollowing the synthetic scheme depicted in FIG. 3.

Compounds of general formula (XIV) are prepared by halogenation ofcompounds of formula (VI) using reagents such as Br₂ orN-halosuccinimide in polar aprotic solvents such as DMF or in mixturesof DMSO-water and at temperatures ranging from 0° C. to 100° C. Thesecompounds correspond to compounds of the invention wherein R² is ahalogen atom.

Compounds of general formula (XV) and in particular those wherein A andB are as hereinabove defined and R² is C₁₋₄alkoxy, C₁₋₄alkylthio, monoor di-C₁₋₄alkylamino or cyano are prepared from compounds of formula(XIV) by nucleophilic displacement of the halogen by the appropriatealcoxide, thioalkoxide, amine or cyanide in solvents such as DMF, DMSOand at temperatures ranging from 0° C. to 180° C.

Compounds of formula (XV) wherein R² is a cyano group can be convertedinto compounds wherein R² is C₁₋₄alkoxy-(CO)— or mono ordi-C₁₋₄alkylamino-(CO)— by hydrolysis followed by esterification oramidation reactions using the corresponding alcohol or aminerespectively.

Compounds of general formula (XV) and in particular those wherein A andB are as hereinabove defined and R² is C₁₋₄alkyl or C₂₋₅alkenyl areprepared from compounds of formula (XIV) by carbon-carbon couplingreaction under Stille-type conditions using the general method describedabove.

Sonogashira-type coupling starting with compounds of formula (XIV)provides the alkynyl derivatives (XVI). Typically Sonogashira couplingtakes place in the presence of the alkynyl derivative of Ra in a solventthat is inert to the reaction conditions such as THF, using an organicbase, preferably triethylamine, copper (preferably copper (I) iodide)and palladium (such as dichlorobis(triphenylphosphine)palladium (II)) ascatalysts. The temperature of the reaction could be from about 70° C. to150° C.

Alternatively compounds of formula (XVII) wherein R² is alkyl may beprepared by catalytic hydrogenation of alkynyl derivatives (XVI) usingcatalysts such as palladium on carbon.

The compounds of formula (XV) and (XVII) are converted into thecompounds of formula (I) by treatment with acylating agents such asanhydrides, acid chlorides, acylcarbonates, isocianates, sulfonylchlorides or sulfamoyl chlorides in apolar organic solvents such as THFor pyridine and in the presence of a convenient organic base (such astriethylamine) or inorganic base at a temperature between 25° C. to 100°C., and eventually acylating with carboxylic acids using coupling agentssuch as diethylcarbodiimide

Compounds of general formula (I) and in particular those of formula(XIX) wherein A and B are as hereinabove defined and R², R¹ and the —NH—group to which R¹ is attached form a moiety of formula (IIb), may beprepared by cyclisation of alkynyl derivatives of general formula (XVI)to compounds of formula (XVIII) mediated by the use of a suitablecatalyst e.g. copper (preferably copper (I) iodide) or palladium inpolar aprotic solvents such as dimethylformamide and at a temperaturerange of 70° C. to 150° C. to provide compounds of general formula(XVIII).

Another alternative method to promote the cyclisation of (XVI) to(XVIII) consists of the use of a suitable base, for example potassiumtert-butoxide, in a polar aprotic solvent such as dimethylformamide or1-methyl-2-pyrrolidinone at temperatures ranging from 60 to 100° C.Compounds of formula (XVIII) can be halogenated using an electrophilicsource of halogen such as NBS, NIS. Further functional grouptransformations using methods known in the art lead to compounds ofgeneral formula (XIX) wherein R_(b) is alkyl. Alternatively compounds ofgeneral formula (XVIII) can be nitrated using HNO₃—H₂SO₄ and theresulting products can be converted into compounds of formula (XIX)wherein R_(b) is C₁₋₄alkylamino, arylC₁₋₄alkylamino and —NH₂ usinggeneral methods known in the art.

Compounds of general formula (I) and in particular those of formula(XXX) wherein A and B are as hereinabove defined and R², R¹ and the —NH—group to which R¹ is attached form a moiety of formula (IIa) may beprepared following the synthetic scheme depicted in FIG. 4.

The aldehydes of formula (XXVIII) are reacted with the halomethylderivatives of formula (XXIX) to yield the ketones of formula (XXIII)either via cyanohydrin intermediates or in a two step process involvingaddition of an organometallic derivative of (XIX), preferably magnesiumor zinc derivative, followed by reoxidation of the resulting alcoholusing oxidating agents such as manganese (IV) oxide.

Alternatively the ketones of formula (XXIII) may be obtained bycondensation of the ethyl esters of formula (XXI) with the compounds offormula (XXII). This reaction is conveniently carried out in thepresence of an organic base such as lithium bis(trimethylsilyl)amide ina range of temperature about −10° C. to about 50° C. and in organicaprotic solvents, preferably tetrahydrofuran or diethyl ether.

The ketones of formula (XXIII) are then oxidized to the diketonederivatives of general formula (XXIV) preferably by reaction withhydrobromic add or N-bromosuccinimide in a polar aprotic solvent such asdimethylsulfoxide in a range of temperature about −10° C. to about 100°C.

Alternatively aldehydes of formula (XXVIII) are reacted with derivativesof formula (XIX) (wherein X represents a trialkylsilyloxy group) toyield the corresponding diol (figure not shown) via addition of anorganometallic derivative of (XIX), preferably lithium derivative.Reoxidation of the resulting diol using oxidating agents such as oxalylchloride, yields the diketone (XXIV).

Further condensation with 1,2,5-thiadiazole-3,4-diamine or1,2,5-oxadiazole-3,4-diamine in a polar protic solvent such as aceticacid at temperatures ranging from 60 to 150° C. provides compounds ofgeneral formula (XXV)

Diaminopyrazines of general formula (XXVI) are obtained by ring openingof compounds of formula (XXV) by treatment with ammonia (when Y═S) or bycatalytic hydrogenation (when Y═O).

Treatment of compounds of formula (XXVI) with acylating agents such asanhydrides, acid chlorides or acylcarbonates in apolar organic solventssuch as THF and in the presence of a convenient organic base (such astriethylamine) or inorganic base, and eventually acylating withcarboxylic acids using coupling agents such as diethylcarbodiimide,yields the compounds of formula (XXVII) which can be converted into thecompounds of formula (XXX) by acid (for example acetic acid) or base(for example sodium hydroxide) catalyzed cyclization at temperaturesbetween 70° C. and 200° C.

Alternatively, diamino derivatives (XXVI) can be cyclized to theimidazopyridines (XXX) by heating in neat trialkylorthoacid or in anacetic acid solution of the orthoacid derivatives and at temperaturesbetween 70° C. and 200° C.

Following other synthetic pathways, treatment of (XXVI) withcarbonylating agents such as carbonyldiimidazole in polar aproticsolvents such as DMF and heating at temperatures between 50° C. and 200°C. provides the imidazolone compounds (XXX) wherein R^(a) is a hydroxygroup.

Alternatively, compounds of general formula (I) and in particular thoseof formula (XXX) wherein A, B are as hereinabove defined and R², R¹ andthe —NH— group to which R¹ is attached form a moiety of formula (IIa)may be prepared following the synthetic scheme depicted in FIG. 5.

Treatment of diaminopyrazine derivatives of formula (XXVI) withthioacylating agents such as thiocarbonyldiimidazole in polar aproticsolvents such as THF and heating at temperatures between 50° C. and 200°C. provides the thioimidazolone compounds (XXXI) that can be transformedto compounds of general formula (XXXII) wherein R^(a) is an alkylthiogroup by treatment with a base such as sodium hydride in polar aproticsolvents such as DMF and in the presence of the corresponding alkylatingagent such as alkyl iodide or bromide. Compounds (XXXII) can betransformed to compounds of general formula (XXX) by direct treatmentwith neat mono or dialkylamines or in the presence of a convenientsolvent at temperatures ranging from 25° C. to 200° C. Alternativelycompounds (XXX) can be obtained by sequential oxidation to thecorresponding sulfones (XXXIII) using oxidizing agents such as m-CPBAand further treatment with mono or dialkylamines under the sameconditions as in the transformation from (XXXII) to (XXX)

Compounds of general formula (I) and in particular those wherein A, Band R² are as hereinabove defined and R¹ represents a group of formula-L-(CR′R″)_(n)-G wherein L represents a direct bond may be preparedfollowing the synthetic scheme depicted in FIG. 6.

Pyrazinones of general formula (XXXIV) can be prepared by diazoniationof aminopyrazines of general formula (XV) with organic or inorganicnitrites such as t-butyl or sodium nitrite and subsequent hydrolysis ofthe corresponding diazonium salt in the presence of an aqueous solutionof an acid such as sulphuric acid. Treatment of pyrazinones (XXXIV) withreagents such as oxalyl chloride, phosphorus oxychloride, phosphoruspentachloride or a combination of them at a temperature ranging from 20°to 150° C. in a solvent like dichloromethane or acetonitrile providesthe halo-derivatives (XXXV) that by treatment with a convenient primaryor secondary amine, preferably in the presence of a palladium catalystsuch as palladium(II) acetate, a phosphine ligand such as BINAP, a basesuch as caesium carbonate in a convenient solvent such as toluene attemperatures ranging from 25 to 200° C. can be converted into thepyrazines of general formula (I)

Experimental Pharmacological Activity Adenosine 2B Receptor SubtypeCompetition Radioligand Binding Assay

A2B membranes were prepared from HEK293 cells stably expressing thehuman A2B receptor that were purchased from Euroscreen (ES-013-C).Competition assays were carried out incubating in polypropylene 96well-plates (n^(o) 267245, NUNC) containing 2 μl of either 1% DMSOsolution, test compound or 100 μM 5′NECA (SIGMA E-2387) for non-specificbinding, 100 μg of A2B-membranes (prepared in Tris-HCl 50 mM pH 6.5,MgCl₂ 10 mM, EDTA 1 mM, benzamidine 0.1 mM; buffer A) and 35 nM[³H]-DPCPX (TRK1064, 128 Ci/mmol, Amersham), in a total volume of 200 μlof buffer A+2 Ul/ml adenosine deaminase, for 60 minutes at roomtemperature. At the end of the incubation, samples were transferred to aGF/C filter plates (Milipore MAFCN0B50) pretreated for 15 min. with 250μl of Tris-HCl 50 mM pH 6.5 (Buffer B). Samples were then filtered 4times with 250 μl of buffer B. Samples were counted using 30 μl ofHisafe II (Perkin Elmer) in a Trilux counter.

The compounds of formula (I) have been tested according to the assaydescribed above and have shown to be potent inhibitors of the A_(2B)adenosine receptor subtype. Preferred pyrazine derivatives of theinvention possess a K_(i) value for the antagonism of A_(2B) (determinedas defined above) of less than 100 nM, preferably less than 30 nM andmore preferably less than 10 nM.

Table 1 shows the binding activities of some of the compounds of thepresent invention determined using the adenosine 2B receptor subtypecompetition radioligand binding assay described above.

TABLE 1 Example K_(i) 3 4 22 16 25 19 67 9 76 4 119 3 142 26 149 0.9

The pyrazine derivatives of the invention are useful in the treatment orprevention of diseases known to be susceptible to improvement bytreatment with an antagonist of the A2_(B) adenosine receptor. Suchdiseases include but are not limited to asthma, chronic obstructivepulmonary disorder, pulmonary fibrosis, emphysema, allergic diseasesincluding allergic rhinitis (perennial, seasonal or occupational),inflammation, pain, reperfusion injury, myocardial ischemia,atherosclerosis, hypertension, retinopathy, diabetes mellitus,inflammatory gastrointestinal tract disorders, cell proliferationdisorders such as cancer, wound healing and/or autoimmune diseases.Examples of autoimmune diseases which can be treated or prevented usingthe compounds of the invention are Addison's disease, autoimmunehemolytic anemia, Crohn's disease, Goodpasture's syndrome, Gravesdisease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura,insulin-dependent diabetes mellitus, multiple sclerosis, myastheniagravis, pemphigus vulgaris, pernicious anemia, poststreptococcalglomerulonephritis, psoriasis, rheumatoid arthritis, scleroderma,Sjogren's syndrome, spontaneous infertility, and systemic lupuserythematosus.

Accordingly, the pyrazine derivatives of the invention andpharmaceutical compositions comprising such compound and/or saltsthereof may be used in a method of treatment of disorders of the humanor animal body which comprises administering to a subject requiring suchtreatment an effective amount of pyrazine derivative of the invention ora pharmaceutically acceptable salt thereof.

The pyrazine derivatives of the invention may also be combined withother active compounds in the treatment of diseases known to besusceptible to improvement by treatment with an antagonist of the A_(2B)adenosine receptor.

The combinations of the invention can optionally comprise one or moreadditional active substances which are known to be useful in thetreatment of respiratory or inflammatory disorders, such as β2-agonists,antagonists of M3 muscarinic receptors, PDE4 inhibitors, corticosteroidsor glucocorticoids, CysLT1 and/or CysLT2 antagonists (also known asleukotriene D4 antagonists), inhibitors of egfr-kinase, p38 kinaseinhibitors, NK1-receptor antagonists, CRTh2 antagonists, syk kinaseinhibitors, CCR3 antagonists, VLA-4 antagonists, H1 antagonists, H4antagonists, 5-Lipoxygenase Inhibitors, A1 adenosine receptorantagonists, A3 adenosine receptor antagonists, A2a adenosine receptoragonists, CCR8 Receptor Antagonists.

When pyrazine derivatives of the invention are used for the treatment ofrespiratory diseases such as asthma, chronic obstructive pulmonarydisorder, pulmonary fibrosis, emphysema it may be advantageous to usethem in combination with other active compounds known to be useful inthe treatment of respiratory diseases such as (1) antagonists of M3muscarinic receptors, (2) β2-agonists, (3) PDE4 inhibitors, (4)cortiocosteroids, (5) CysLT1 and/or CysLT2 antagonists, (6) inhibitorsof egfr-kinase, (7) p38 kinase inhibitors, (8) NK1 receptor agonists,(9) CRTh2 antagonists, (10) syk kinase inhibitors, (11) CCR3antagonists, (12) VLA-4 antagonists, (13) H1 antagonists, (14) H4antagonists, (15) 5-Lipoxygenase Inhibitors, (16) A1 adenosine receptorantagonists, (17) A3 adenosine receptor antagonists, (18) A2a adenosinereceptor agonists and (19) CCR8 Receptor Antagonists.

When formulating combinations with the pyrazine derivatives of thepresent invention it is particularly preferred to combine the pyrazinederivatives with an active compound selected from the group consistingof antagonists of M3 muscarinic receptors, β2-agonists, H1 antagonists,H4 antagonists, cortiocosteroids and CysLT1 and/or CysLT2 antagonists(also known as leukotriene D4 antagonists).

Combinations of the pyrazine derivatives of the present invention withCysLT1 and/or CysLT2 antagonists, H1 antagonists and/or H4 antagonistsare particularly good in the treatment of respiratory diseases by oraladministration.

Combinations of the pyrazine derivatives of the present invention withcorticosteroids, β2-agonists and/or M3 antagonists are particularly goodin the treatment of respiratory diseases by inhalation.

Examples of suitable β2-agonists that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare: arformoterol, bambuterol, bitolterol, broxaterol, carbuterol,clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaprotenerol, nolomirole, orciprenaline, pirbuterol, procaterol,reproterol, ritodrine, rimoterol, salbutamol, salmefamol, salmeterol,sibenadet, sotenerot, sulfonterol, terbutaline, tiaramide, tulobuterol,GSK-597901, GSK-159797, HOKU-81,(−)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamidehydrochloride monohydrate, carmoterol, QAB-149 and5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanoland1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanoloptionally in the form of their racemates, their enantiomers, theirdiastereomers, and mixtures thereof, and optionally theirpharmacologically-compatible acid addition salts and the compoundsclaimed in Spanish Patent application numbers P200501229 and P200601082.When the β2-agonists are in the form of a salt or derivative It isparticularly preferred that it is in a form selected from the sodiumsalts, sulfobenzoates, phosphates, isonicotinates, acetates,propionates, dihydrogen phosphates, palmitates, pivalates, fumarates,furoates, xinafoates or mixtures thereof.

The following β2-agonists are of special interest for the combinationwith the compounds of formula (I): arformoterol, bambuterol, bitolterol,broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol,hexoprenaline, ibuterol, isoprenaline, levosalbutamol, mabuterol,meluadrine, nolomirole, orciprenaline, pirbuterol, procaterol,(R,R)-formoterol, reproterol, ritodrine, rimoterol, salbutamol,salmeterol, sibenadet, sulfonterol, terbutaline, tulobuterol,GSK-597901, GSK-159797, KUL-1248, TA-2005 and QAB-149 optionally in theform of their racemates, their enantiomers, their diastereomers, andmixtures thereof, and optionally their pharmacologically-compatible acidaddition salts

It is preferred that they compounds of the present invention arecombined with long-acting β2-agonists (also known as LABAs). Thecombined drugs could thus be administered once a day.

It is also of interest that the β2-agonists are selected from the groupconsisting of fenoterol, formoterol, hexoprenaline, salmeterol,GSK-597901, GSK-159797,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexyloxy}-butyl)benzene-sulfonamide,QAB-149,5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl-]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,(−)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamidehydrochloride monohydrate, carmoterol, or an enantiomer, racemate,pharmacologically acceptable acid addition salt, hydrate, or mixturethereof.

Still most preferred are the following β2-agonists: formoterol,salmeterol and GSK-597901, GSK-159797, QAB-149 optionally in the form oftheir racemates, their enantiomers, their diastereomers and mixturesthereof, and optionally their pharmacologically-compatible acid additionsalts. Still more preferred are salmeterol and formoterol.

The following can be considered to represent examples of suitable acidfor the formation of addition salts: hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanosulphonic acid, aceticacid, fumaric acid, succinic acid, lactic acid, citric acid or maleicacid. Furthermore, mixtures of the aforementioned acids can be used.

A particularly preferred embodiment of the present invention is acombination of an antagonist of the A2_(B) adenosine receptor of thepresent invention with a LABA selected from formoterol, salmeterol,GSK-597901, GSK-159797,(−)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)ethylamino]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetamidehydrochloride monohydrate, carmoterol, QAB-149 and5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one.

Still most preferred is a combination of an antagonist of the A2_(B)adenosine receptor of the present invention with a LABA selected fromformoterol, salmeterol, GSK-597901, GSK-159797 and QAB-149. It is afurther particularly preferred embodiment of the present invention thecombination of an antagonist of the A2_(B) adenosine receptor of thepresent invention with either formoterol or salmeterol.

Examples of suitable M3 antagonists (anticholinergics) that can becombined with the antagonists of the A2_(B) adenosine receptor of thepresent invention are tiotropium salts, oxitropium salts, flutropiumsalts, ipratropium salts, glycopyrronium salts, trospium salts,revatropate, espatropate,3-[2-Hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanesalts,1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octanesalts, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acidendo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester salts (DAU-5884),3-(4-Benzylpiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one(NPC-14695),N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1(R)-cyclopentyl]-2-hydroxy-2-phenylacetamide(J-104135),2(R)-Cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide(J-106366),2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide(J-104129),1-[4-(2-Aminoethyl)piperidin-1-yl]-2(R)-[3,3-difluorocyclopent-1(R)-yl]-2-hydroxy-2-phenylethan-1-one(Banyu-280634),N—[N-[2-[N-[1-(Cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3-triphenylpropionamide(Banyu CPTP), 2(R)-Cyclopentyl-2-hydroxy-2-phenylacetic acid4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057),UCB-101333, Merck's OrM3,7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonanesalts,7-(2,2-diphenylpropionyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonanesalts,7-hydroxy-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonane9-methyl-9H-fluorene-9-carboxylic acid ester salts, all of themoptionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof, and optionally in the form of theirpharmacologically-compatible acid addition salts. Among the saltschlorides, bromides, iodides and methanesulphonates are preferred.

Examples of suitable PDE4 inhibitors that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare denbufylline, rolipram, cipamfylline, arofylline, filaminast,piclamilast, mesopram, drotaverine hydrochloride, lirimilast,cilomilast, 6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylicacid,(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine,N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide,9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine,N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide,N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide,3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purinehydrochloride,4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluororomethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol,ONO-6126 (Eur Respir J 2003, 22 (Suppl. 45): Abst 2557) and thecompounds claimed in the PCT patent application numbers WO03/097613,WO2004/058729 A1 and WO 2005/049581 A1.

Examples of suitable corticosteroids and glucocorticoids that can becombined with the antagonists of the A2_(B) adenosine receptor of thepresent invention are prednisolone, methylprednisolone, dexamethasone,naflocort, deflazacort, halopredone acetate, budesonide, beclomethasonedipropionate, hydrocortisone, triamcinolone acetonide, fluocinoloneacetonide, fluocinonide, clocortolone pivalate, methylprednisoloneaceponate, dexamethasone palmitoate, tipredane, hydrocortisoneaceponate, prednicarbate, alclometasone dipropionate, halometasone,methylprednisolone suleptanate, mometasone furoate, rimexolone,prednisolone famesylate, ciclesonide, deprodone propionate, fluticasonepropionate, halobetasol propionate, loteprednol etabonate, betamethasonebutyrate propionate, flunisolide, prednisone, dexamethasone sodiumphosphate, triamcinolone, betamethasone 17-valerate, betamethasone,betamethasone dipropionate, hydrocortisone acetate, hydrocortisonesodium succinate, prednisolone sodium phosphate and hydrocortisoneprobutate.

Examples of suitable CysLT1 and/or CysLT2 antagonists that can becombined with the antagonists of the A2_(B) adenosine receptor of thepresent invention are tomelukast, Ibudilast, pobilukast, pranlukasthydrate, zafirlukast, ritolukast, verlukast, sulukast, tipelukast,cinalukast, iralukast sodium, masilukast, montelukast sodium,5-[3-[3-(2-Quinolinylmethoxy)phenoxy]propyl]-1H-tetrazole,(E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]vinyl]-2-(1H-tetrazol-5-yl)-4H-benzopyran-4-onesodium salt,2-[N-[4-(4-Chlorophenylsulfonamido)butyl]-N-[3-(4-isopropylthiazol-2-ylmethoxy)benzyl]sulfamoyl]benzoicacid,(3R,4R)-3-[6-(5-Fluorobenzothiazol-2-ylmethoxy)-4-hydroxy-3,4-dihydro-2H-1-benzopyran-3-ylmethyl]benzoicacid,2-[2-[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxymethyl]phenyl]aceticacid hydrochloride,5-[2-[4-(Quinolin-2-ylmethoxy)phenoxymethyl]benzyl]-1H-tetrazole,(E)-2,2-Diethyl-3′-[2-[2-(4-isopropyl)thiazolyl]ethenyl]succinanilicacid;4-[4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutyricacid,[[5-[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]aceticacid,9-[(4-Acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,5-[3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl]-8-(N,N-dimethylcarbamoyl)-4,6-dithiaoctanoicacid sodium salt;3-[1-[3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxopropylsulfanyl]methylsulfanyl]propionicacid sodium salt,6-(2-Cyclohexylethyl)-[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(1H)-one,(R)-3-[2-Methoxy-4-[N-(2-methylphenylsulfonyl)carbamoyl]benzyl]-1-methyl-N-(4,4,4-trifluoro-2-methylbutyl)indole-5-carboxamide,MCC-847 (from AstraZeneca),(+)-4(S)-(4-Carboxyphenylthio)-7-[4-(4-phenoxybutoxy)phenyl]-5(Z)-heptenoicacid and the compounds claimed in PCT patent applicationWO2004/043966A1.

Examples of suitable inhibitors of egfr-kinase that can be combined withthe antagonists of the A2_(B) adenosine receptor of the presentinvention are palifermin, cetuximab, gefitinib, repifermin, erlotinibhydrochloride, canertinib dihydrochloride, lapatinib, andN-[4-(3-Chloro-4-fluorophenylamino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)-2(E)-butenamide.

Examples of suitable p38 kinase inhibitors that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare chlormethiazole edisylate, doramapimod,5-(2,6-Dichlorophenyl)-2-(2,4-difluorophenylsulfanyl)-6H-pyrimido[3,4-b]pyridazin-6-one,4-Acetamido-N-(tert-butyl)benzamide, SCIO-469 (described in ClinPharmacol Ther 2004, 75 (2): Abst PII-7 and VX-702 described inCirculation 2003, 108 (17, Suppl. 4): Abst 882 and the compounds claimedin Spanish patent application number P200600396.

Examples of suitable NK1-receptor antagonists that can be combined withthe antagonists of the A2_(B) adenosine receptor of the presentinvention are nolpitantium besilate, dapitant, lanepitant, vofopitanthydrochloride, aprepitant, ezlopitant,N-[3-(2-Pentylphenyl)propionyl]-threonyl-N-methyl-2,3-dehydrotyrosyl-leucyl-D-phenylalanyl-allo-threonyl-asparaginyl-serineC-1.7-O-3.1 lactone,1-Methylindol-3-ylcarbonyl-[4-(R)-hydroxy]-L-prolyl-[3-(2-naphthyl)]-L-alanineN-benzyl-N-methylamide,(+)-(2S,3S)-3-[2-Methoxy-5-(trifluoromethoxy)benzylamino]-2-phenylpiperidine,(2R,4S)—N-[1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)piperidin-4-yl]quinoline-4-carboxamide,3-[2(R)-[1(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-phosphinicacid bis(N-methyl-D-glucamine) salt;[3-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinylmethyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonicacid 1-deoxy-1-(methylamino)-D-glucitol (1:2) salt,1′-[2-[2(R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl]spiro[benzo[c]thiophen-1(3H)-4′-piperidine]2(S)-oxidehydrochloride and the compound CS-003 described in Eur Respir J 2003, 22(Suppl. 45): Abst P2664.

Examples of suitable CRTh2 antagonists that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare2-[5-Fluoro-2-methyl-1-[4-(methylsulfonyl)phenylsulfonyl]-1H-indol-3-yl]aceticacid, Ramatroban,[(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4tetrahydrocyclopenta[b]indol-3-yl]aceticacid and(1R,2R,3S,5S)-7-[2-(5-Hydroxybenzothiophen-3-ylcarboxamido)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5(Z)-heptenoicacid

Examples of suitable Syk kinase inhibitors that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare piceatannol,2-(2-Aminoethylamino)-4-[3-(trifluoromethyl)phenylamino]pyrimidine-5-carboxamide,R-091 (from Rigel), R-112 (from Rigel), R-343 (from Rigel), R-788 (fromRigel),6-[5-Fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-3-onebenzenesulfonate,1-(2,4,6-Trihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1-one,N-[4-[6-(Cyclobutylamino)-9H-purin-2-ylamino]phenyl]-N-methylacetamide,2-[7-(3,4-Dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-ylamino]pyridine-3-carboxamidedihydrochloride and AVE-0950 (from Sanofi-Aventis).

Examples of CCR3 antagonists that can be combined with the antagonistsof the A2_(B) adenosine receptor of the present invention are4-[3-[4-(3,4-Dichlorobenzyl)morpholin-2(S)-ylmethyl]ureidomethyl]benzamide,N-[1(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl]-N′-(3,4,5-trimethoxyphenyl)urea,N-[1(S)-[4-(4-Chlorobenzyl)piperidin-1-ylmethyl]-2-hydroxpropyl]-N′-(3,4,5-trimethoxyphenyl)urea,3-[3-(3-Acetylphenyl)ureido]-2-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-N-methylbenzamide,4-(3,4-Dichlorobenzyl)-1-methyl-1-[3-methyl-2(R)-[3-(3,4,5-trimethoxyphenyl)ureido]butyl]piperidiniumchloride,N-[2-[4(R)-(3,4-Dichlorobenzyl)pyrrolidin-2(S)-yl]ethyl]-2-[5-(3,4-dimethoxyphenyl]pyrimidin-2-ylsulfanyl]acetamide,CRIC-3 (from IPF Pharmaceuticals),2(R)-[1-[1-(2,4-Dichlorobenzyl)-4(S)-(3-thienyl)pyrrolidin-3(S)-ylmethyl]piperidin-4-ylmethyl]pentanoicacid,8-[1-(2,4-Dichlorobenzyl)-4(S)-(3-thienyl)pyrrolidin-3(S)-ylmethyl]-3,3-dipropyl-1-oxa-8-azaspiro[4.5]decane-2(S)-carboxylicacid,11-[1-(2,4-Dichlorobenzyl)-4(S)-(3-thienyl)pyrrolidin-3(S)-ylmethyl]-3,14-dioxa-11-azadispiro[5.1.5.2]pentadecane-15(S)-carboxylicacid, W-56750 (from Mitsubishi Pharma),N-[1(S)-[3endo-(4-Chlorobenzyl)-8-azabicyclo[3.2.1]oct-8-ylmethyl]-2(S)-hydroxpropyl]-N′-(3,4,5-trimethoxyphenyl)urea,N-(3-Acetylphenyl)-N′-[(1R,2S)-2-[3(S)-(4-fluorobenzyl)piperidin-1-ylmethyl]cyclohexyl]ureabenzenesulfonate,trans-1-(Cycloheptylmethyl)-4-(2,7-dichloro-9H-xanthen-9-ylcarboxamido)-1-methylpiperidiniumiodide, GW-782415 (from GlaxoSmithKline), GW-824575 (fromGlaxoSmithKline),N-[1′-(3,4-Dichlorobenzyl)-1,4′-bipiperidin-3-ylmethyl]quinoline-6-carboxamide,N-[1-(6-Fluoronaphthalen-2-ylmethyl)pyrrolidin-3(R)-yl]-2-[1-(3-hydroxy-5-methylpyridin-2-ylcarbonyl)piperidin-4-ylidene]acetamidefumarate and DIN-106935 (from Bristol-Myers Squibb).

Examples of VLA-4 antagonists that can be combined with the antagonistsof the A2_(B) adenosine receptor of the present invention areN-[4-[3-(2-Methylphenyl)ureido]phenylacetyl]-L-leucyl-L-aspartyl-L-valyl-L-proline,3(S)-[2(S)-[4,4-Dimethyl-3-[4-[3-(2-methylphenyl)ureido]benzyl]-2,5-dioxoimidazolidin-1-yl]-4-methylpentanoylamino]-3-phenylpropionicacid,2(S)-(2,6-Dichlorobenzamido)-3-(2′,6′-dimethoxybiphenyl-4-yl)propionicacid, RBx-4638 (from Ranbaxy), R-411 (from Roche), RBx-7796 (fromRanbaxy), SB-683699 (from GlaxoSmithKline), DW-908e (from DaiichiPharmaceutical), RO-0270608 (from Roche), AJM-300 (from Ajinomoto),PS-460644 (from Pharmacopeia) and the compounds claimed in PCT patentapplication numbers WO 02/057242 A2 and WO 2004/099126 A1.

Examples of H1 antagonists that can be combined with the antagonists ofthe A2_(B) adenosine receptor of the present invention are carebastine,azelastine hydrochloride, acrivastine, emedastine fumarate; emedastinedifumarate, loratadine, picumast dihydrochloride, cyproheptadinehydrochloride, diphenhydramine hydrochloride, doxepin hydrochloride,promethazine hydrochloride, rocastine fumarate, fenclozine maleate,levocabastine hydrochloride, desloratadine, cinnarizine, setastinehydrochloride, tagorizine, mizolastine, ebastine, cetirizinehydrochloride, tazifylline hydrochloride, epinastine hydrochloride,olopatadine hydrochloride,11-(1-Acetyl-4-piperidylidene)-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine,noberastine, pibaxizine, flezelastine hydrochloride, alcaftadine,mapinastine maleate, bepotastine besilate;3-[4-(8-Fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperidin-1-yl]propionicacid dehydrate, rupatadine fumarate, triprolidine hydrochloride,LAS-X-113 (from Almirall Prodesfarma), terfenadine carboxylatehydrochloride; fexofenadine hydrochloride,1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]piperidine-3(R)-carboxylicacid, bilastine, levocetirizine; ketotifen, azatadine maleate,clemastine fumarate,5,6-Dihydrospiro[1H-imidazo[2,1-b][3]benzazepine-11,4′-piperidine]-3-carboxamidedihydrochloride, chlorpheniramine maleate;5-[4-(N-Carbamoyl-N-hydroxyamino)-1-butynyl]-2-[2-[4-[1(R)-(4-chlorophenyl)-1-phenylmethyl]piperazin-1-yl]ethoxy]benzamide,K-123 (from Kowa) and the products claimed in PTC patent applicationnumbers WO 00/75130 A1, WO 02/36589 A1, WO 03/099807 A1 and WO 03/082867A1.

Examples of H4 antagonists that can be combined with the antagonists ofthe A2_(B) adenosine receptor of the present invention are[3-(4-Chlorophenyl)propyl][3-(1H-imidazol-4-yl)propyl]ether,1-(5-Chloro-1H-indol-2-yl)-1-(4-methylpiperazin-1-yl)methanone and1-(5-Chloro-1H-benzimidazol-2-yl)-1-(4-methylpiperazin-1-yl)methanone.

Examples of 5-lipoxygensase inhibitors that can be combined with theantagonists of the A2_(B) adenosine receptor of the present inventionare

6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone, tebufelone,zileuton,6-Hydroxy-4,5,7-trimethyl-2-(4-sulfamoylbenzylamino)benzothiazolehydrochloride, 3,5,6-Trimethyl-2-(3-pyridylmethyl)-1,4-benzoquinonehydrochloride, darbufelone mesilate, etalocib sodium, licofelone,4-[3-Fluoro-5-[4-(2-methyl-1H-imidazol-1-yl)phenylsulfanyl]phenyl]tetrahydro-2H-pyran-4-carboxamidehydrochloride,5-[4-(N-Carbamoyl-N-hydroxyamino)-1-butynyl]-2-[2-[4-[1(R)-(4-chlorophenyl)-1-phenylmethyl]piperazin-1-yl]ethoxy]benzamide,UP-0483/0530 (from Unigen Pharmaceuticals) and PEP-03 (fromPharmaengine).

Examples of A1 adenosine receptor antagonists that can be combined withthe antagonists of the A2_(B) adenosine receptor of the presentinvention are doxofylline, theophylline,(+)-2(R)-(2-Hydroxyethyl)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine;8-(3-Oxocyclopentyl)-1,3-dipropylxanthine;8-(3-Oxocyclopentyl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione,8-Cyclopentyl-1,3-dipropylxanthine;8-Cyclopentyl-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione,3-[2-(3-Carboxypropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine;8-(Octahydro-2,5-methanopentalen-3a-yl)-1,3-dipropylxanthine;(±)—N6-(endo-2-Norbornyl)-9-methyladenine;(±)—N6-(Bicyclo[2.2.1]hept-2-yl)-9-methyladenine;2-[1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoyl]piperidin-2(R)-yl]aceticacid, apaxifylline, naxifylline, DTI-0017 (from Aderis), SLV-320 (fromSolvay) and3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]propionicacid.

Examples of A3 adenosine receptor antagonists that can be combined withthe antagonists of the A2_(B) adenosine receptor of the presentinvention areN-[9-Chloro-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazolin-5-yl]-2-phenylacetamide,5-Butyl-8-(4-chlorophenyl)-1H-[1,2,4]triazolo[5,1-i]purine,5-Butyl-8-[4-(trifluoromethyl)phenyl]-1H-[1,2,4]triazolo[5,1-i]purine,N-[4-(3-Methylphenyl)-5-(4-pyridyl)thiazol-2-yl]acetamide,4-(3,4-Dichlorophenyl)-5-(4-pyridinyl)thiazol-2-amine,3-[5-(2-Methyl-1H-imidazol-1-yl)-2-(pyrazin-2-ylamino)thiazol-4-yl]benzonitrileand SSR-161421(from Sanofi-Aventis).

Examples of A2a adenosine receptor agonists that can be combined withthe antagonists of the A2_(B) adenosine receptor of the presentinvention are 2-(1-Octynyl)adenosine, binodenoson,(1S,2R,3S,4R)-4-[7-[1(R)-(3-Chloro-2-thienylmethyl)propylamino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentane-1-carboxamide,GW-328267 (from GlaxoSmithKline), apadenoson, regadenoson,2-[2-(4-Chlorophenyl)ethoxy]adenosine, UK-432097 (from Pfizer).

Examples of chemokine CCR8 receptor antagonists that can be combinedwith the antagonists of the A2_(B) adenosine receptor of the presentinvention are3-[1-(1H-Indo)-2-ylmethyl)piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)oxazolidin-2-one,5-(6-Methoxyquinolin-4-yl)-3-[1-(1-methyl-1H-indol-2-ylmethyl)piperidin-4-yl]oxazolidin-2-one,5-(6-Methoxyquinolin-4-yl)-3-[1-(3-phenylpropyl)piperidin-4-yl]oxazolidin-2-one,3-[1-(1H-Indol-2-ylmethyl)piperidin-4-yl]-5-(6-methoxy-1,5-naphthyridin-4-yl)oxazolidin-2-one,3-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-5-(6-methoxy-1,5-naphthyridin-4-yl)oxazolidin-2-one,3-[1-(4-Bromobenzyl)piperidin-4-yl]-5-(6-methoxy-1,5-naphthyridin-4-yl)oxazolidin-2-one,3-[1-(3-Chloro-4-methoxybenzyl)piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)oxazolidin-2-one,5-(6-Methoxyquinolin-4-yl)-3-[1-(4-methylbenzyl)piperidin-4-yl]oxazolidin-2-one,3-[1-(3,5-Dimethylbenzyl)piperidin-4-yl]-5-(6-methoxyquinolin-4-yl)oxazolidin-2-one,N-[4-[N-(3-Methoxyphenyl)sulfamoyl]naphthalen-1-yl]benzamide,N-[4-[N-[1-(Morpholin-4-ylcarbonyl)piperidin-4-yl]sulfamoyl]naphthalen-1-yl]benzamide,2-Methyl-N-[4-[N-(1-propionylpiperidin-4-yl)sulfamoyl]naphthalen-1-yl]benzamide,2-Methyl-N-[4-[N-[1-[2-(1-pyrrolidinyl)acetyl]piperidin-4-yl]sulfamoyl]naphthalen-1-yl]benzamide,cis-3-Methyl-4-[4-(3-methylpyridin-2-ylcarboxamido)naphthalen-1-ylsulfonamido]piperidine-1-carboxylicacid ethyl ester,N-[4-(N-Cyclohexylsulfamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl]cyclohexanecarboxamide,2-Methyl-N-[4-[N-(tetrahydropyran-4-yl)sulfamoyl]-5,6,7,8-tetrahydronaphthalen-1-yl]benzamide,N-[5-(N-Cyclohexylsulfamoyl)naphthalen-1-yl]benzamide,3-[7-(2-Methylbenzamido)-2,3-dihydro-1H-inden-4-ylsulfonamido]pyrrolidine-1-carboxylicacid tert-butyl ester,N-[4-(N-Benzylsulfamoyl)naphthalen-1-yl]benzamide,N-[4-[N-[1-(Cyclopentylcarbonyl)piperidin-4-yl]sulfamoyl]naphthalen-1-yl]benzamide,4-[4-(2-Methylbenzamido)naphthalen-1-ylsulfonamido]-N-propylpiperidine-1-carboxamide,N-[4-[N-(1-Butyrylpiperidin-4-yl)sulfamoyl]naphthalen-1-yl]-2-methoxybenzamide,N-[4-[N-[1-[2(S)-Aminobutyryl]piperidin-4-yl]sulfamoyl]naphthalen-1-yl]-2-methylbenzamide,cis-N-[4-[N-(1-Butyryl-3-methylpiperidin-4-yl)sulfamoyl]naphthalen-1-yl]-3-methylpyridine-2-carboxamide,N-[4-[N-(4-Methoxyphenyl)sulfamoyl]-5,6,7,8-tetrahydronaphthalen-1-yl]benzamide,4-[4-(2,3-Dimethylbenzamidomethyl)naphthalen-1-ylsulfonamido]piperidine-1-carboxylicacid ethyl ester,4-[4-(Benzylaminomethyl)naphthalen-1-ylsulfonamido]piperidine-1-carboxylicacid ethyl ester,N-[3-(4-Butyl-1,4-diazepan-1-ylcarbonyl)phenyl]-3,4-dichlorobenzenesulfonamide,3-Bromo-N-[3-(4-butyl-1,4-diazepan-1-ylcarbonyl)phenyl]benzenesulfonamide,N-[3-(4-Hexyl-1,4-diazepan-1-ylcarbonyl)phenyl]-3,4-dimethoxybenzenesulfonamide,4-Chloro-2,5-dimethyl-N-[3-[4-(2-phenylethyl)-1,4-diazepan-1-ylcarbonyl]phenyl]benzenesulfonamide,N-[3-(4-Ethyl-1,4-diazepan-1-ylcarbonyl)phenyl]-3,4-dimethoxybenzenesulfonamide,N-[5-(4-Butyl-1,4-diazepan-1-ylcarbonyl)-2-methylphenyl]-3,4-dimethoxybenzenesulfonamide,N-[5-[4-(Cyclopropylmethyl)-1,4-diazepan-1-ylcarbonyl]-2-methylphenyl]-3,4-dimethoxybenzenesulfonamide,N-[4-Bromo-3-(4-butyl-1,4-diazepan-1-ylcarbonyl)phenyl]-3,4-dimethoxybenzenesulfonamide,N-[3-(4-Butyl-1,4-diazepan-1-ylcarbonyl)phenyl]-4-chloro-2,5-dimethylbenzenesulfonamide,N-[3-(4-Ethyl-1,4-diazepan-1-ylcarbonyl)phenyl]naphthalene-2-sulfonamide,N-[3-[4-(Cyclopropylmethyl)-1,4-diazepan-1-ylcarbonyl]phenyl]naphthalene-2-sulfonamide,N-[5-(4-Butyl-1,4-diazepan-1-ylcarbonyl)-2-methylphenyl]naphthalene-2-sulfonamide,N-[5-(4-Butyl-1,4-diazepan-1-ylcarbonyl)-2-chlorophenyl]naphthalene-2-sulfonamide,N-[5-[4-(Cyclopropylmethyl)-1,4-diazepan-1-ylcarbonyl]-2-methylphenyl]naphthalene-2-sulfonamide,N-[5-(4-Butyl-1,4-diazepan-1-ylcarbonyl)-2-methylphenyl]-1,3-benzodioxole-5-sulfonamide,N-[4-Bromo-3-(4-propyl-1,4-diazepan-1-ylcarbonyl)phenyl]naphthalene-2-sulfonamide,N-[4-Chloro-3-(4-pentyl-1,4-diazepan-1-ylcarbonyl)phenyl]naphthalene-2-sulfonamideandN-[5-(4-Ethyl-1,4-diazepan-1-ylcarbonyl)-2-methylphenyl]-2,3-dihydro-1,4-benzodioxine-6-sulfonamide.

The combinations of the invention may be used in the treatment ofdisorders which are susceptible to amelioration by antagonism of A2_(B)receptors. Thus, the present application encompasses methods oftreatment of these disorders, as well as the use of the combinations ofthe invention in the manufacture of a medicament for the treatment ofthese disorders.

Preferred examples of such disorders are those respiratory diseases,wherein the use of bronchodilating agents is expected to have abeneficial effect, for example asthma, acute or chronic bronchitis,emphysema, or Chronic Obstructive Pulmonary Disease (COPD).

The active compounds in the combinations of the invention may beadministered by any suitable route, depending on the nature of thedisorder to be treated, e.g. orally (as syrups, tablets, capsules,lozenges, controlled-release preparations, fast-dissolving preparations,lozenges, etc); topically (as creams, ointments, lotions, nasal spraysor aerosols, etc); by injection (subcutaneous, intradermic,intramuscular, intravenous, etc.) or by inhalation (as a dry powder, asolution, a dispersion, etc).

The active compounds in the combination, i.e. the A2_(B) receptorantagonist of the invention, and the other optional active compounds maybe administered together in the same pharmaceutical composition or indifferent compositions intended for separate, simultaneous, concomitantor sequential administration by the same or a different route.

One execution of the present invention consists of a kit of partscomprising an antagonist of A2_(B) receptor antagonists of the presentinvention together with instructions for simultaneous, concurrent,separate or sequential use in combination with another active compounduseful in the treatment of a respiratory disease which responds toA2_(B) antagonism.

Another execution of the present invention consists of a packagecomprising an antagonist of A2_(B) receptors of formula (I) and anotheractive compound useful in the treatment of a respiratory disease for thesimultaneous, concurrent, separate or sequential use in the treatment ofa respiratory disease which responds to A2_(B) antagonism.

In a preferred embodiment of the invention the active compounds in thecombination are administered by inhalation through a common deliverydevice, wherein they can be formulated in the same or in differentpharmaceutical compositions.

In the most preferred embodiment the A2_(B) receptor antagonist of theinvention and the other active compound as defined above are bothpresent in the same pharmaceutical composition and are administered byinhalation through a common delivery device.

The pharmaceutical formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. All methods include the step of bringing the activeingredient(s) into association with the carrier. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A syrup formulation will generally consist of a suspension or solutionof the compound or salt in a liquid carrier for example, ethanol, peanutoil, olive oil, glycerine or water with flavouring or colouring agent.

Where the composition is in the form of a tablet, any pharmaceuticalcarrier routinely used for preparing solid formulations may be used.Examples of such carriers include magnesium stearate, talc, gelatine,acacia, stearic acid, starch, lactose and sucrose.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Where the composition is in the form of a capsule, any routineencapsulation is suitable, for example using the aforementioned carriersin a hard gelatine capsule. Where the composition is in the form of asoft gelatine capsule any pharmaceutical carrier routinely used forpreparing dispersions or suspensions may be considered, for exampleaqueous gums, celluloses, silicates or oils, and are incorporated in asoft gelatine capsule.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine or blisters of for example laminated aluminium foil, for use inan inhaler or insufflator. Formulations generally contain a powder mixfor inhalation of the compound of the invention and a suitable powderbase (carrier substance) such as lactose or starch. Use of lactose ispreferred. Each capsule or cartridge may generally contain between 2 μgand 150 μg of each therapeutically active ingredient. Alternatively, theactive ingredient (s) may be presented without excipients.

Packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered or metered in use. Dry powder inhalers are thus classifiedinto three groups: (a) single dose, (b) multiple unit dose and (c) multidose devices.

For inhalers of the first type, single doses have been weighed by themanufacturer into small containers, which are mostly hard gelatinecapsules. A capsule has to be taken from a separate box or container andinserted into a receptacle area of the inhaler. Next, the capsule has tobe opened or perforated with pins or cutting blades in order to allowpart of the inspiratory air stream to pass through the capsule forpowder entrainment or to discharge the powder from the capsule throughthese perforations by means of centrifugal force during inhalation.After inhalation, the emptied capsule has to be removed from the inhaleragain. Mostly, disassembling of the inhaler is necessary for insertingand removing the capsule, which is an operation that can be difficultand burdensome for some patients. Other drawbacks related to the use ofhard gelatine capsules for inhalation powders are (a) poor protectionagainst moisture uptake from the ambient air, (b) problems with openingor perforation after the capsules have been exposed previously toextreme relative humidity, which causes fragmentation or indenture, and(c) possible inhalation of capsule fragments. Moreover, for a number ofcapsule inhalers, incomplete expulsion has been reported (e.g. Nielsenet al, 1997).

Some capsule inhalers have a magazine from which individual capsules canbe transferred to a receiving chamber, in which perforation and emptyingtakes place, as described in WO 92/03175. Other capsule inhalers haverevolving magazines with capsule chambers that can be brought in linewith the air conduit for dose discharge (e.g. WO91/02558 and GB2242134). They comprise the type of multiple unit dose inhalers togetherwith blister inhalers, which have a limited number of unit doses insupply on a disk or on a strip.

Blister inhalers provide better moisture protection of the medicamentthan capsule inhalers. Access to the powder is obtained by perforatingthe cover as well as the blister foil, or by peeling off the cover foil.When a blister strip is used instead of a disk, the number of doses canbe increased, but it is inconvenient for the patient to replace an emptystrip. Therefore, such devices are often disposable with theincorporated dose system, including the technique used to transport thestrip and open the blister pockets.

Multi-dose inhalers do not contain pre-measured quantities of the powderformulation. They consist of a relatively large container and a dosemeasuring principle that has to be operated by the patient. Thecontainer bears multiple doses that are isolated individually from thebulk of powder by volumetric displacement. Various dose measuringprinciples exist, including rotatable membranes (e.g. EP0069715) ordisks (e.g. GB 2041763; EP 0424790; DE 4239402 and EP 0674533),rotatable cylinders (e.g. EP 0166294; GB 2165159 and WO 92/09322) androtatable frustums (e.g. WO 92/00771), all having cavities which have tobe filled with powder from the container. Other multi dose devices havemeasuring slides (e.g. U.S. Pat. No. 5,201,308 and WO 97/00703) ormeasuring plungers with a local or circumferential recess to displace acertain volume of powder from the container to a delivery chamber or anair conduit e.g. EP 0505321, WO 92/04068 and WO 92/04928.

Reproducible dose measuring is one of the major concerns for multi doseinhaler devices.

The powder formulation has to exhibit good and stable flow properties,because filling of the dose measuring cups or cavities is mostly underthe influence of the force of gravity.

For reloaded single dose and multiple unit dose inhalers, the dosemeasuring accuracy and reproducibility can be guaranteed by themanufacturer. Multi dose inhalers on the other hand, can contain a muchhigher number of doses, whereas the number of handlings to prime a doseis generally lower.

Because the inspiratory air stream in multi-dose devices is oftenstraight across the dose measuring cavity, and because the massive andrigid dose measuring systems of multi dose inhalers can not be agitatedby this inspiratory air stream, the powder mass is simply entrained fromthe cavity and little de-agglomeration is obtained during discharge.

Consequently, separate disintegration means are necessary. However inpractice, they are not always part of the inhaler design. Because of thehigh number of doses in multi-dose devices, powder adhesion onto theinner walls of the air conduits and the de-agglomeration means must beminimized and/or regular cleaning of these parts must be possible,without affecting the residual doses in the device. Some multi doseinhalers have disposable drug containers that can be replaced after theprescribed number of doses has been taken (e.g. WO 97/000703). For suchsemi-permanent multi dose inhalers with disposable drug containers, therequirements to prevent drug accumulation are even stricter.

Apart from applications through dry powder inhalers the compositions ofthe invention can be administered in aerosols which operate viapropellant gases or by means of so-called atomisers, via which solutionsof pharmacologically-active substances can be sprayed under highpressure so that a mist of inhalable particles results. The advantage ofthese atomisers is that the use of propellant gases can be completelydispensed with.

Such atomisers are described, for example, in PCT Patent Application No.WO 91/14468 and International Patent Application No. WO 97/12687,reference here being made to the contents thereof.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the active ingredient (s) and a suitablepropellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic acid or lecithin and cosolvens eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10μ, preferably 2-5μ. Particles having asize above 20μ are generally too large when inhaled to reach the smallairways. To achieve these particle sizes the particles of the activeingredient as produced may be size reduced by conventional means eg bymicronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline.

Achieving high dose reproducibility with micronised powders is difficultbecause of their poor flowability and extreme agglomeration tendency. Toimprove the efficiency of dry powder compositions, the particles shouldbe large while in the inhaler, but small when discharged into therespiratory tract. Thus, an excipient such as lactose or glucose isgenerally employed. The particle size of the excipient will usually bemuch greater than the inhaled medicament within the present invention.When the excipient is lactose it will typically be present as milledlactose, preferably crystalline alpha lactose monohydrate.

Pressurized aerosol compositions will generally be filled into canistersfitted with a valve, especially a metering valve. Canisters mayoptionally be coated with a plastics material e.g. a fluorocarbonpolymer as described in WO96/32150. Canisters will be fitted into anactuator adapted for buccal delivery.

Typical compositions for nasal delivery include those mentioned abovefor inhalation and further include non-pressurized compositions in theform of a solution or suspension in an inert vehicle such as wateroptionally in combination with conventional excipients such as buffers,anti-microbials, tonicity modifying agents and viscosity modifyingagents which may be administered by nasal pump.

Typical dermal and transdermal formulations comprise a conventionalaqueous or non-aqueous vehicle, for example a cream, ointment, lotion orpaste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer asingle dose.

The amount of each active which is required to achieve a therapeuticeffect will, of course, vary with the particular active, the route ofadministration, the subject under treatment, and the particular disorderor disease being treated.

Effective doses are normally in the range of 1-2000 mg of activeingredient per day. Daily dosage may be administered in one or moretreatments, preferably from 1 to 4 treatments, per day. Preferably, theactive ingredients are administered once or twice a day.

Each dosage unit may contain for example from 0.1 mg to 1000 mg andpreferably from 1 mg to 100 mg of a pyrazine derivative of the inventionor a pharmaceutical acceptable salt thereof.

When combinations of actives are used, it is contemplated that allactive agents would be administered at the same time, or very close intime. Alternatively, one or two actives could be taken in the morningand the other (s) later in the day. Or in another scenario, one or twoactives could be taken twice daily and the other (s) once daily, eitherat the same time as one of the twice-a-day dosing occurred, orseparately. Preferably at least two, and more preferably all, of theactives would be taken together at the same time. Preferably, at leasttwo, and more preferably all actives would be administered as anadmixture.

The active substance compositions according to the invention arepreferably administered in the form of compositions for inhalationdelivered with the help of inhalers, especially dry powder inhalers;however, any other form or parenteral or oral application is possible.Here, the application of inhaled compositions embodies the preferredapplication form, especially in the therapy of obstructive lung diseasesor for the treatment of asthma.

The syntheses of the compounds of the invention and of the intermediatesfor use therein are illustrated by the following Examples (1 to 160)including Preparation Examples (Intermediates 1 to 30) which do notlimit the scope of the invention in any way.

¹H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercuryspectrometer operating at 200 MHz. Melting points were recorded using aBüchi B-540 apparatus. The chromatographic separations were obtainedusing a Waters 2795 system equipped with a Symmetry C18 (2.1×100 mm, 3.5mm) column. As detectors a Micromass ZMD mass spectrometer using ESionization and a Waters 996 Diode Array detector were used. The mobilephase was formic acid (0.46 ml), ammonia (0.115 ml) and water (1000 ml)(A) and formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) andacetonitrile (500 ml) (B): initially from 0% to 95% of B in 20 min, andthen 4 min. with 95% of B. The reequilibration time between twoinjections was 5 min. The flow rate was 0.4 ml/min. The injection volumewas 5 μl. Diode array chromatograms were processed at 210 nm.

PREPARATION EXAMPLES Preparation 1 Step a

6-(3-Fluorophenyl)pyrazin-2-amine

To a stirred solution of 2-amino-6-chloropyrazine (2.0 g, 15.43 mmol) ina mixture of toluene (90 mL) and ethanol (8.5 mL) was added3-fluorophenyl boronic acid (2.60 g, 18.51 mmol) and a 2M aqueoussolution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture wassubjected to three cycles of evacuation-backfilling with argon, andtetrakis(triphenylphosphine)palladium (0.713 g, 0.617 mmol) was added.The mixture was subjected again to three cycles ofevacuation-backfilling with argon the flask was capped and placed in a110° C. oil bath. After 4 h, the mixture was cooled, partitioned betweendichloromethane and water the organic layer was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by silica gel flashchromatography (33% ethyl acetate in hexanes to 50% ethyl acetate inhexanes). Concentration in vacuo of the product-rich fractions providedthe titled compound (2.79 g, 95%) as a yellowish solid (2.79 g, 95%).

δ ¹H-NMR (CDCl₃): 8.38 (s, 1H), 7.95 (s, 1H), 7.60 (m, 2H), 7.40 (m,1H), 4.65 (s, 2H).

Step b

5-Bromo-6-(3-fluorophenyl)pyrazin-2-amine

To a 0° C. cooled stirred solution of6-(3-fluorophenyl)pyrazin-2-ylamine (0.5 g, 2.64 mmol) in a mixture ofDMSO (10 mL) and water (0.25 mL), was added N-bromosuccinimide (0.518 g,2.90 mmol) in portions. After stirring for 5 h, the mixture was pouredinto water, the precipitate collected by filtration, washed with waterand dried to give the title compound as a yellow solid (0.60 g, 85%).

δ ¹H-NMR (CDCl₃): 7.65 (s, 1H), 7.4 (m, 3H), 7.05 (m, 1H), 4.70 (s, 2H).

ESI/MS m/e: 268 ([M+H]⁺, C₁₀H₇BrFN₃).

Preparation 2 Step a

6-(2-Furyl)pyrazin-2-amine

Obtained as a yellowish solid (65%) from 6-chloropyrazin-2-ylamine and2-furylboronic acid following the procedure of Preparation 1, step a.

δ ¹H-NMR (CDCl₃): 8.25 (s, 1H), 7.80 (s, 1H), 7.48 (d, 1H), 7.00 (d,2H), 6.48 (m, 1H), 4.62 (bs, 2H).

Step b

5-Bromo-6-(2-furyl)pyrazin-2-amine

Obtained as a brown solid (44%) from 6-furylpyrazin-2-ylamine andN-bromo succinimide following the procedure of Preparation 1, step b.

δ ¹H-NMR (CDCl₃): 7.62 (d, 2H), 7.58 (d, 1H), 7.58 (m, 1H), 4.75 (bs,2H).

Preparation 3 Step a

6-(2-Thienyl)pyrazin-2-amine

Obtained as a yellowish solid (39%) from 6-chloropyrazin-2-ylamine andthiophen-2-boronic acid following the procedure of Preparation 1, stepa.

δ ¹H-NMR (CDCl₃): 8.02 (s, 1H), 7.61 (d, 1H), 7.42 (d, 1H), 7.05 (m,1H), 5.05 (br, 2H).

Step b

5-Bromo-6-(2-thienyl)pyrazin-2-amine

Obtained as a brown solid (14%) from 6-thiophen-2-ylpyrazin-2-ylamineand N-bromo succinimide following the procedure of Preparation 1, stepb.

δ ¹H-NMR (CDCl₃): 8.35 (s, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.43 (d,1H), 7.15 (m, 1H), 4.60 (br, 2H).

Preparation 4

1-[5-Amino-3-(2-furyl)pyrazin-2-yl]ethanone

To a stirred solution of 5-bromo-6-(2-furyl)pyrazin-2-amine (Preparation2, 1.5 g, 6.3 mmol) in a mixture of DMF (16 mL) and water (4 mL) wasadded butyl vinyl ether (4.10 mL, 31.5 mmol), potassium acetate (3.80mL, 7.56 mmol), 1,3-bis-(diphenylphosphino)propane (0.172 g, 0.416 mmol)and palladium(II) acetate (42.0 mg, 0.189 mmol)¹. The mixture wassubjected to three cycles of evacuation-backfilling with argon andheated at 122° C. under microwave irradiation. After 4 h, the mixturewas cooled to room temperature and hydrolyzed by adding of HCl 2N (30mL) for 30 min. The mixture was then neutralized with a saturatedsolution of potassium carbonate and diluted with dichloromethane. Theorganic layer was separated, dried (Na₂SO₄) and evaporated. The residuewas purified by silica gel flash chromatography (2% methanol indichloromethane). Concentration in vacuo of the product-rich fractionsprovided the titled compound as a pale-yellow solid (0.77 g, 60%). ¹K.S. A. Vallin, M. Larhed, A. Hallberg, J. Org. Chem., 2001, 66, 4340.

δ ¹H-NMR (CDCl₃): 7.85 (s, 1H), 7.60 (d, 1H), 7.15 (d, 1H), 6.55 (dd,1H), 5.05 (bs, 2H), 2.60 (s, 3H).

ESI/MS m/e: 204 ([M+H]⁺, C₁₀H₉N₃O₂)

Preparation 5 Step a

6-Pyridin-2-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with2-amino-6-chloropyrazine (1.00 g, 7.72 mmol),2-(tributylstannyl)pyridine (3.55 g, 7.72 mmol) and xylene (40 mL). TheSchlenk tube was subjected to three cycles of evacuation-backfillingwith argon, and tetrakis(triphenylphosphine)palladium (446 mg, 0.38mmol) was added. After three new cycles of evacuation-backfilling withargon, the Schlenk tube was capped and placed in a 150° C. oil bath.After 20 h, the mixture was cooled, partitioned between water and ethylacetate, the aqueous phase was extracted twice with ethyl acetate, theorganic layers washed with brine, dried (MgSO₄) and evaporated. Silicagel flash chromatography (dichloromethane/methanol 98:2 todichloromethane/methanol 90:10) provided the title compound as a lightbrown solid (950 mg, 71%).

δ ¹H-NMR (CDCl₃): 8.90 (s, 1H), 8.70 (d, 1H), 8.20 (d, 1H), 8.00 (s,1H), 7.80 (dd, 1H). 7.30 (m, 1H), 4.65 (s, 2H).

ESI/MS m/e: 173 ([M+H]⁺, C₉H₈N₄)

Step b

5-Bromo-6-pyridin-2-ylpyrazin-2-amine

Obtained as a brown solid (36%) from 6-pyridin-2-ylpyrazin-2-amine andN-bromosuccinimide following the procedure of Preparation 1, step b.

δ ¹H-NMR (CDCl₃): 8.75 (d, 1H), 7.8 (m, 3H), 7.35 (m, 1H), 4.75 (s, 2H).

ESI/MS m/e: 252 ([M+H]⁺, C₉H₇BrN₄)

Preparation 6 Step a

6-Pyridin-3-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with6-chloropyrazin-2-amine (0.73 g, 5.71 mmol), 3-pyridineboronic acid(0.91 g, 7.42 mmol), dioxane (50 mL) and a 2M aqueous solution of cesiumcarbonate (8.5 mL, 17.13 mmol). The Schlenk tube was subjected to threecycles of evacuation-backfilling with argon, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (290 mg, 0.35 mmol) was added. After three newcycles of evacuation-backfilling with argon, the Schlenk tube was cappedand placed in a 90° C. oil bath. After 16 h, the mixture was cooled,partitioned between water and ethyl acetate, the aqueous phase extractedtwice with ethyl acetate, the organic layers washed with brine, dried(MgSO₄) and evaporated. The residue was purified by silica gel flashchromatography (95:5 dichloromethane/methanol) to give the titlecompound (845 mg, 86%) as a solid.

δ ¹H-NMR (CDCl₃): 9.18 (s, 1H), 8.67 (d, 1H), 8.38 (s, 1H), 8.25 (m,1H), 7.99 (s, 1H), 7.41 (m, 1H), 4.77 (s, 2H).

ESI/MS (m/e, %): 172 [(M+1)⁺, C₉H₈N₄].

Step b

5-Bromo-6-pyridin-3-ylpyrazin-2-amine

Obtained as a brown solid (72%) from 6-pyridin-3-ylpyrazin-2-amine andN-bromosuccinimide following the procedure of Preparation 1, step b.

δ ¹H-NMR (CDCl₃): 8.93 (s, 1H), 8.65 (d, 1H), 8.10 (m, 1H), 7.80 (s,1H), 7.43 (dd, 1H).

ESI/MS (m/e, %): 251 [(M+1)⁺, C₉H₇BrN₄]

Preparation 7 Step a

6-Chloro-5-iodo-4-ylpyrazin-2-amine

To a 0° C. cooled stirred solution of 2-amino-6-chloropyrazine (3 g, 23mmol) in a mixture of DMSO (90 mL) and water (2.2 mL), was addedN-iodosuccinimide (5.2 g, 23 mmol) in portions. After stirring for 72 h,the mixture was poured into water, extracted twice with ethyl acetate,the organic layers washed with brine, dried (MgSO₄) and evaporated.Flash chromatography (98:2 dichloromethane/methanol) furnished the titlecompound as a yellow solid (4.43 g, 76%).

δ ¹H-NMR (CDCl₃): 7.73 (s, 1H), 4.72 (s, 2H).

ESI/MS (m/e, %): 255 [(M+1)⁺, C₄H₃ClIN₃].

Step b

6-Chloro-5-pyridin-4-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with6-chloro-5-iodo-4-ylpyrazin-2-amine (1.68 g, 6.57 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.61 g, 7.89mmol), dioxane (120 mL) and a 2M aqueous solution of cesium carbonate(10 mL, 20 mmol). The Schlenk tube was subjected to three cycles ofevacuation-backfilling with argon, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex [PdCl2dppf.DCM] (322 mg, 0.39 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in a 90° C. oil bath. After 20 h, the mixturewas cooled, partitioned between water and ethyl acetate, the aqueousphase extracted twice with ethyl acetate, the organic layers washed withbrine, dried (MgSO₄) and evaporated. The residue was triturated withdiethyl ether and methanol and the precipitate was collected byfiltration and dried to furnish the title compound as a light brownsolid (0.85 g, 63%).

δ ¹H-NMR (DMSO-d₆): 8.60 (d, 2H), 7.95 (s, 1H), 7.65 (d, 2H), 7.20 (s,2H).

ESI/MS m/e: 206 ([M+H]⁺, C₉H₇ClN₄)

Preparation 8

N-(6-Chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide

To a stirred solution of 6-chloro-5-pyridin-4-ylpyrazin-2-amine(Preparation 7, 0.73 g, 3.56 mmol) in pyridine (15 mL) was addedcyclopropanecarbonyl chloride (648 μL, 7.1 mmol). The solution wasstirred at 70° C. for 1 h 30 min, evaporated, partitioned betweendichloromethane and a 4% sodium bicarbonate aqueous solution, theaqueous phase extracted twice with dichloromethane, the organic layerswashed with brine, dried (MgSO₄) and evaporated. The residue wastriturated with diethyl ether and methanol and the precipitate wascollected by filtration and dried to furnish the title compound as alight brown solid (0.69 g, 70%).

δ ¹H-NMR (DMSO-d₆): 9.55 (s, 1H), 8.75 (d, 2H), 8.55 (s, 1H), 7.75 (d,2H), 1.65 (m, 1H), 1.2 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 274 ([M+H]⁺, C₁₃H₁₁ClN₄O)

Preparation 9

6-Chloro-5-(3-chloropyridin-4-yl)pyrazin-2-amine

An oven dried resealable Schlenk tube was charged with6-chloro-5-iodo-4-ylpyrazin-2-amine (Preparation 7 step a, 1.02 g, 3.98mmol), 3-cloro-4-(tributylstannyl)pyridine⁽¹⁾ (1.76 g, 4.38 mmol) anddimethylformamide (15 mL). The Schlenk tube was subjected to threecycles of evacuation-backfilling with argon, andbis(triphenylphosphino)-palladium (II) chloride (129 mg, 0.185 mmol) andcopper (I) iodide (77 mg, 0.040 mmol) were added. After three new cyclesof evacuation-backfilling with argon, the Schlenk tube was capped andplaced in a 160° C. oil bath. After 20 h, the mixture was cooled,partitioned between water and ethyl acetate, the aqueous phase extractedtwice with ethyl acetate, the organic layers washed twice with water,brine, dried (MgSO₄) and evaporated. Silica gel flash chromatography(98:2 dichloromethane/methanol) provided the title compound as a solid(0.72 g, 74%). ⁽¹⁾ Prepared according to Yue et. al. Org. Lett. 2002, 4(13), 2201-2203.

δ ¹H-NMR (CDCl₃): 8.72 (s, 1H), 8.59 (d, 1H), 7.99 (s, 1H), 7.35 (d,1H), 4.95 (s, 2H).

ESI/MS (m/e, %): 240 [(M+1)⁺, C₉H₆Cl₂N₄].

Preparation 10 Step a

6-Chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-amine

Obtained as a yellowish solid (57%) from6-chloro-5-iodo-4-ylpyrazin-2-amine and3-fluoro-4-(tributylstannyl)pyridine⁽²⁾ following the procedure ofPreparation 9. ⁽²⁾ Prepared according to EP1104754 (Reference Example197)

δ ¹H-NMR (DMSO-d₆): 8.65 (s, 1H), 8.45 (d, 1H), 7.90 (s, 1H), 7.55 (t,1H), 7.30 (s, 2H).

ESI/MS m/e: 224 ([M+H]⁺, C₉H₆ClFN₄)

Step b

N-[6-Chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a brown solid (78%) from6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-amine andcyclopropanecarbonyl chloride (607 μL, 6.67 mmol) following the sameprocedure as in Preparation 8.

δ ¹H-NMR (CDCl₃): 9.58 (s, 1H), 8.62 (s, 1H), 8.58 (d, 1H), 8.22 (bs,1H), 7.50 (dd, 1H), 1.65 (m, 1H), 1.2 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 292 ([M+H]⁺, C₁₃H₁₀ClFN₄O)

Preparation 11 Step a

1-(3-Fluorophenyl)-2-pyridin-4-ylethanone

To a solution of ethyl 3-fluorobenzoate (2.0 g, 11.9 mmol) and4-methylpyridine (1.1 mL, 1.0 g, 10.8 mmol) in THF (9 mL) at 0° C. undernitrogen atmosphere was added dropwise lithium bis(trimethylsilyl)amide(23.8 mL, 1.0M in hexane, 23.8 mmol) During the addition a precipitatewas formed and the suspension was stirred at room temperature overnight.The reaction was diluted with hexane (40 mL) and filtered. The solid waspartitioned between ethyl acetate and a saturated solution of ammoniumchloride. The organic phase was dried (MgSO₄) and evaporated underreduced pressure to give the title compound as a yellow solid (2.09 g,82%).

δ ¹H-NMR (CDCl₃): 8.58 (d, 2H), 7.75 (m, 1H), 7.46 (m, 1H), 7.28 (m,2H), 7.20 (d, 2H), 4.26 (s, 2H).

ESI/MS m/e: 216 ([M+H]⁺, C₁₃H₁₀FNO)

Step b

1-(3-Fluorophenyl)-2-pyridin-4-ylethane-1,2-dione

Hydrobromic acid (7.9 mL, 48% in H₂O, 69.7 mmol) was added with cautionto a stirred solution of 1-(3-fluorophenyl)-2-pyridin-4-ylethanone (5.0g, 23.2 mmol) in DMSO (40 mL) at 55° C. The reaction was stirred for 2 hand then allowed to cool to room temperature. Water was added and theaqueous phase was neutralized with solid sodium carbonate and extractedtwice with ethyl acetate. The organic extracts were washed with brine,dried (MgSO₄) and evaporated under reduced pressure to provide the titlecompound as a yellow solid (2.85 g, 67%).

δ ¹H-NMR (CDCl₃): 8.88 (d, 2H), 7.79 (d, 2H), 7.72 (m, 2H), 7.60-7.34(m, 2H).

GC/MS m/e: 229 (M⁺, C₁₃H₈FNO₂)

Step c

5-(3-Fluorophenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

A mixture of 1-(3-fluorophenyl)-2-pyridin-4-ylethane-1,2-dione (1.5 g,6.5 mmol) and 1,2,5-thiadiazole-3,4-diamine (1.1 g, 9.8 mmol) in AcOH(30 mL) was stirred and heated at reflux for 1 h. The mixture was cooledto room temperature and the solvent was removed under reduced pressure.The residue was partitioned between ethyl acetate and a solution ofNaHCO3 4%. The organic phase was dried (MgSO₄) and evaporated to drynessto give the title compound as a dark oil (1.7 g, 82%).

δ ¹H-NMR (CDCl₃): 8.68 (d, 2H), 7.81 (m, 2H), 7.44 (d, 2H), 7.40-7.20(m, 2H).

ESI/MS m/e: 216 ([M+H]⁺, C₁₅H₈FN₅S)

Preparation 12 Step a

1-Phenyl-2-pyridin-4-ylethane-1,2-dione

Obtained (74%) from 1-phenyl-2-pyridin-4-ylethanone following theprocedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.90 (d, 2H), 8.00 (d, 2H), 7.79 (d, 2H), 7.71 (d,1H), 7.68 (t, 2H).

Step b

5-Phenyl-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (97%) from 1-phenyl-2-pyridin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

ESI/MS m/e: 292 ([M+H]+, C₁₅H₃N₅S)

Preparation 13 Step a

4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)pyridine

A mixture of pyridin-4-ylmethanol (8.0 g, 73 mmol),tert-butyldimethylsilyl chloride (14.3 g, 95 mmol) and imidazole (12.9g, 0.19 mol) in DMF (40 mL) was stirred overnight at room temperature.The reaction was poured onto water and extracted twice with ethylacetate. The combined organic phases were dried (MgSO₄) and evaporatedunder reduced pressure to yield the title compound as yellow oil (7.5 g,46%).

δ ¹H-NMR (CDCl₃): 8.42 (d, 2H), 7.19 (d, 2H), 4.64 (s, 2H), 0.81 (brs,12H), 0.00 (s, 6H).

Step b

1-(4-Fluorophenyl)-2-pyridin-4-ylethane-1,2-diol

To a cooled solution (−78° C.) of diisopropylamine (6.3 mL, 4.5 g, 45mmol), n-butyllithium (30 mL, 1.6 N in hexanes) was added dropwise undernitrogen atmosphere. After stirring for 30 min. at 0° C., the mixturewas cooled to −20° C. and a solution of4-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (7.5 g, 34 mmol) inTHF (24 mL) was added dropwise. 30 min later a solution of4-fluorobenzaldehyde (4.4 mL, 5.1 g, 41 mmol) in THF (10 mL) was finallyadded. The reaction was allowed to reach room temperature and quenchedwith water and a saturated solution of ammonium chloride. The crudeproduct was recovered with diethyl ether.

The resulting yellow oil was redissolved in THF (210 mL) and treatedwith TBAF. 3H₂O (5.4 g, 17 mmol) stirring at room temperature for 1hour. The solvent was evaporated under vacuum and the residuepartitioned between water and ethyl acetate. The organic phase was dried(MgSO₄), concentrated and the solid obtained was washed with diethylether to provide the title compound as a yellow solid (4.0 g, 51%).

ESI/MS m/e: 234 ([M+H]⁺, C₁₃H₁₂FO₂)

Step c

1-(4-Fluorophenyl)-2-pyridin-4-ylethane-1,2-dione

To a stirred cooled solution (−60° C.) of oxalyl chloride (3.55 mL, 40.8mmol) in CH₂Cl₂ (16 mL) a solution of dimethyl sulfoxide (4.0 mL) inCH₂Cl₂ was added dropwise. Five minutes later a solution of1-(4-fluorophenyl)-2-pyridin-4-ylethane-1,2-diol (4.0 g, 17 mmols) inDMSO/CH₂Cl₂ (32 mL/13 mL) was dropped. The mixture was allowed to stirfor 30 min at −60° C. and then triethylamine (24 mL) was added. When thereaction reached room temperature was diluted with water anddichloromethane. The organic phases were washed with water and brine anddried (MgSO₄). After removal of the solvent under vacuum, the resultingsolid was triturated with hexane to afford the title compound as anorange solid (3.68 g, 94%).

δ ¹H-NMR (CDCl₃): 8.90 (d, 2H), 8.01 (m, 2H), 7.79 (d, 2H), 7.22 (dd,2H).

Step d

5-(4-Fluorophenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained as an orange solid (81%) from1-(4-fluorophenyl)-2-pyridin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

ESI/MS m/e: 310 ([M+H]⁺, C₁₅H₈FN₅S)

Preparation 14 Step a

1-(3-Methylphenyl)-2-pyridin-4-ylethane-1,2-dione

Obtained (73%) from 1-(3-methylphenyl)-2-pyridin-4-ylethanone followingthe procedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.87 (d, 2H), 7.79 (d+s, 2H+2H), 7.48 (m, 2H), 2.41(s, 3H).

Step b

5-(3-Methylphenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained from 1-(3-methylphenyl)-2-pyridin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

δ ¹H-NMR (CDCl₃): 8.64 (d, 2H), 7.43 (d+s, 2H+1H), 7.32-7.18 (m, 3H),2.38 (s, 3H).

ESI/MS m/e: 306 ([M+H]⁺, C₁₆H₁₁N₅S)

Preparation 15 Step a

1-(2-Fluorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione

Obtained (93%) from1-(2-fluorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethanone followingthe procedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.81 (d, 1H), 8.10 (t, 1H), 7.64 (m+d, 1H+1H), 7.39(t, 1H), 7.26 (s, 1H), 7.15 (t, 1H), 2.22 (s, 3H).

ESI/MS m/e: 277 ([M+H]+, C₁₃H₃FN₂O₂S)

Step b

5-(2-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (97%) from1-(2-fluorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

δ ¹H-NMR (CDCl₃): 8.79 (d, 1H), 7.96-7.84 (m, 2H), 7.49-7.38 (m, 2H),6.98 (t, 3H), 1.91 (s, 3H).

Preparation 16 Step a

1-(3-Chlorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione

Obtained (77%) from1-(3-chlorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethanone, followingthe procedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.85 (d, 1H), 7.91 (s, 1H), 7.77 (d, 1H), 7.66-7.63(m, 2H), 7.50 (t, 1H), 2.36 (s, 3H).

Step b

5-(3-Chlorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (39%) from1-(3-chlorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

ESI/MS m/e: 373 ([M+H]+, C₁₅H₉ClN₆S₂)

Preparation 17 Step a

2-(3-Fluorophenyl)-1-[2-(methylthio)pyrimidin-4-yl]ethanone

Following the same procedure as in Preparation 11, step a, the titlecompound was obtained (88% yield) from ethyl 3-fluorobenzoate and4-methyl-2-(methylthio) pyrimidine.

δ ¹H-NMR (CDCl₃): exists as a 2:1 mixture of enol:keto tautomers: 8.44(d, 1H, keto form), 8.34 (d, 1H, enol form), 7.88-7.03 (m, 4H, enol+ketoform), 6.99 (d, 1H, keto form), 6.63 (d, 1H, enol form), 5.98 (s, 1H,enol from), 4.36 (s, 2H, keto form), 2.98 (s, 3H, enol+keto form).

ESI/MS m/e: 263 ([M+H]⁺, C₁₃H₁₁FN₂OS)

Step b

1-(3-Fluorophenyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione

Following the same procedure as in Preparation 11, step b, the titlecompound was obtained after purification of the crude by silica gelchromatography eluting with 5% MeOH/CH₂Cl₂ to afford the title compoundas yellow oil (0.34 g, 10%).

δ ¹H-NMR (CDCl₃): 8.83 (d, 1H), 7.62 (d, 1H), 7.62-7.36 (m, 4H), 2.36(s, 3H).

GC/MS m/e: 276 ([M+H]⁺, C₁₃H₉FN₂O₂S)

Step c

5-(3-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine

Following the same procedure as in Preparation 11, step c, the titlecompound was obtained after purification of the crude by silica gelcolumn chromatography with hexane/AcOEt 3:1 to afford the title compoundas a yellow solid (0.21 g, 47%).

ESI/MS m/e: 357 ([M+H]⁺, C₁₅H₉FN₆S₂)

Preparation 18 Step a

1-(2-Furyl)-2-pyridin-4-ylethanone

Obtained as an orange solid (75%) from ethyl 2-furoate and4-methylpyridine following the procedure described in Preparation 11,step a.

δ ¹H-NMR (DMSO-d₆): 8.50 (d, 2H), 8.04 (s, 1H), 7.66 (m, 1H), 7.32 (d,2H), 6.78 (m, 1H).

ESI/MS m/e: 188 ([M+H]⁺, C₁₁H₉NO₂)

Step b

1-(2-Furyl)-2-pyridin-4-ylethane-1,2-dione

Obtained as a brown solid (78%) from 1-(2-furyl)-2-pyridin-4-ylethanonefollowing the procedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.86 (d, 2H), 7.84 (d, 2H+s, 1H), 7.52 (d, 1H), 6.64(d, 1H).

GC/MS m/e: 201 (M⁺, C₁₁H₇NO₃)

Step c

5-(2-Furyl)-6-pyridin-4-yl[1,2,5]thiadiazoio[3,4-b]pyrazine

Obtained as a brown solid (92%) from1-(2-furyl)-2-pyridin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

δ ¹H-NMR (DMSO-d₆): 8.78 (d, 2H), 7.81 (m, 2H), 7.96 (s, 1H), 7.62 (s,1H), 6.70 (m, 2H).

ESI/MS m/e: 282 ([M+H]⁺, C₁₃H₇N₃OS)

Preparation 19 Step a

1-(5-Methyl-2-furyl)-2-pyridin-4-ylethane-1,2-dione

Obtained (28%) from 1-(5-methyl-2-furyl)-2-pyridin-4-ylethanone (crudeproduct), following the procedure described in Preparation 11, step b.

GC/MS m/e: 215 (M⁺, C₁₂H₉NO₃)

Step b

5-(5-Methyl-2-furyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (82%) from 1-(5-methyl-2-furyl)-2-pyridin-4-ylethane-1,2-dioneand 1,2,5-thiadiazole-3,4-diamine, following the procedure described inPreparation 11, step c.

ESI/MS m/e: 296 ([M+H]⁺, C₁₄H₉N₅OS)

Preparation 20 Step a

1-(1-Benzofuran-2-yl)-2-pyridin-4-ylethane-1,2-dione

Obtained (87%) from 1-(1-benzofuran-2-yl)-2-pyridin-4-ylethanone,following the procedure described in Preparation 11, step b.

GC/MS m/e: 251 ([M+H]⁺, C₁₅H₉NO₃)

Step b

5-(1-Benzofuran-2-yl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (74%) from 1-(1-benzofuran-2-yl)-2-pyridin-4-ylethane-1,2-dioneand 1,2,5-thiadiazole-3,4-diamine, following the procedure described inPreparation 11, step c.

ESI/MS m/e: 332 ([M+H]+, C₁₇H₉N₅OS)

Preparation 21 Step a

1-Pyridin-3-yl-2-pyridin-4-ylethane-1,2-dione

Obtained (30%) from 1-pyridin-3-yl-2-pyridin-4-ylethanone following theprocedure described in Preparation 11, step b.

GC/MS m/e: 212 (M⁺, C₁₂H₂N₂O₂)

Step b

5-Pyridin-3-yl-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (55%) from 1-pyridin-3-yl-2-pyridin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine, following the procedure described inPreparation 11, step c.

ESI/MS m/e: 293 ([M+H]⁺, C₁₄H₈N₆S)

Preparation 22 Step a

1-(2-Furyl)-2-pyrimidin-4-ylethanone

Obtained as a yellow solid (91%) from ethyl 2-furoate and4-methylpyrimidine following the procedure described in Preparation 11,step a.

δ ¹H-NMR (DMSO-d₈) exists as a 1.2:1 mixture of enol:keto tautomers:enolform: 14.6 (brs, 1H), 9.09 (s, 1H), 8.63 (brs, 1H), 8.78 (d, 1H), 8.03(s, 1H), 7.62 (d, 1H), 7.04 (m, 1H), 6.63 (brs, 1H), 6.01 (s, 1H); ketoform: 8.78 (d, 1H), 8.21 (d, 1H), 7.86 (s, 1H), 7.58 (d, 1H), 7.04 (m,1H), 6.79 (m, 1H), 4.40 (s, 2H)

ESI/MS m/e: 189 ([M+H]⁺, C₁₀H₈N₂O₂)

Step b

1-(2-Furyl)-2-pyrimidin-4-ylethane-1,2-dione

Obtained as a brown oil (82%) from 1-(2-furyl)-2-pyrimidin-4-ylethanonefollowing the procedure described in Preparation 11, step b.

ESI/MS m/e: 203 ([M+H]⁺, C₁₀H₆N₂O₃)

Step c

5-(2-Furyl)-6-pyrimidin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained as a brown solid (82%) from1-(2-furyl)-2-pyrimidin-4-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

δ ¹H-NMR (DMSO-d₆): 9.05 (s, 1H), 8.90 (d, 1H), 7.79 (d, 1H), 7.59 (s,1H), 6.78 (m, 1H), 6.45 (m, 1H).

ESI/MS m/e: 283 ([M+H]⁺, C₁₂H₆N₆OS)

Preparation 23 Step a

1-(2-Furyl)-2-[2-(methylthio)pyrimidin-4-yl]ethanone

Obtained as a yellow solid (73%) from ethyl 2-furoate and4-methyl-2-(methylthio) pyrimidine following the procedure described inPreparation 11, step a.

δ ¹H-NMR (CDCl₃): (most in enol form): 7.89 (d, 1H), 7.18 (brs, 1H),6.59 (m, 1H), 6.24 (d, 1H), 6.20 (brs, 1H), 5.41 (s, 1H), 2.21 (s, 1H).

ESI/MS m/e: 235 ([M+H]⁺, C₁₁H₁₀N₂O₂S)

Step b

1-(2-Furyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione

Obtained as a brown oil (68%) from1-(2-furyl)-2-[2-(methylthio)pyrimidin-4-yl]ethanone following theprocedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.82 (d, 1H), 7.79 (d, 1H), 6.62 (d, 1H), 7.40 (d,1H), 6.65 (d, 1H), 2.20 (s, 3H).

ESI/MS m/e: 249 ([M+H]⁺, C₁₁H₈N₂O₃S)

Step c

5-(2-Furyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained as a brown solid (82%) from1-(2-furyl)-2-[2-(methylthio)pyrimidin-4-yl]ethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure described inPreparation 11, step c.

δ ¹H-NMR (CDCl₃): 8.80 (d, 1H), 7.59 (d, 1H), 7.47 (s, 1H), 7.21 (brs,1H), 6.59 (brs, 1H), 2.34 (s, 3H).

ESI/MS m/e: 329 ([M+H]⁺, C₁₃H₈N₈OS₂)

Preparation 24 Step a

1-(3-Methyl-2-furyl)-2-pyrimidin-4-ylethane-1,2-dione

Obtained (91%) from 1-(3-methyl-2-furyl)-2-pyrimidin-4-ylethanone,following the procedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 9.39 (s, 1H), 9.10 (d, 1H), 8.03 (d, 1H), 7.50 (s,1H), 6.52 (s, 1H), 2.46 (s, 3H).

GC/MS m/e: 216 ([M+H]+, C₁₁H₈N₂O₃)

Step b

5-(3-Methyl-2-furyl)-6-pyrimidin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (80%) from1-(3-methyl-2-furyl)-2-pyrimidin-4-ylethane-1,2-dione, following theprocedure described in Preparation 11, step c.

ESI/MS m/e: 297 ([M+H]⁺, C₁₃H₈N₆OS)

Preparation 25 Step a

1-[2-(Methylthio)pyrimidin-4-yl]-2-(2-thienyl)ethane-1,2-dione

Obtained (99%) from2-[2-(methylthio)pyrimidin-4-yl]-1-(2-thienyl)ethanone, following theprocedure described in Preparation 11, step b.

δ ¹H-NMR (CDCl₃): 8.82 (d, 1H), 7.89 (d, 1H), 7.68 (brs, 1H), 7.61 (d,1H), 7.10 (brs, 1H), 2.21 (s, 3H).

Step b

5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained (70%) from1-[2-(methylthio)pyrimidin-4-yl]-2-(2-thienyl)ethane-1,2-dione,following the procedure described in Preparation 11, step c.

δ ¹H-NMR (DMSO-d₆): 8.99 (d, 1H), 7.91 (d, 1H), 7.72 (d, 1H), 7.13 (dd,1H), 6.88 (brs, 1H), 2.39 (s, 3H).

ESI/MS m/e: 332 ([M+H]+, C₁₇H₃N₃OS)

Preparation 26

Step a

6-Chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-amine

Obtained as an orange oil (42%) from 6-chloro-5-iodo-4-ylpyrazin-2-amineand 3,5-difluoro-4-(tributylstannyl)pyridine following the procedure ofPreparation 9.

¹H-NMR (CDCl₃): 8.50 (s, 1H), 7.70 (m, 1H), 7.50 (m, 1H), 5.20 (s, 2H).

ESI/MS m/e: 242 ([M+H]⁺, C₉H₅ClF₂N₄).

Step b

N-[6-Chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a light yellow solid (40%) from6-Chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-amine andcyclopropanecarbonyl chloride following the same procedure ofPreparation 8.

¹H-NMR (CDCl₃): 9.60 (s, 1H), 8.45 (s, 2H), 8.20 (s, 1H), 1.60 (m, 1H),1.20 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 311[M+H]⁺, C₁₃H₉ClF₂N₄O)

Preparation 27 Step aN-(5-Bromo-6-pyridin-3-ylpyrazin-2-yl)cyclopropanecarboxamide

Obtained as a white solid (79%) from5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6) andcyclopropanecarbonyl chloride following the same procedure ofPreparation 8.

Step bN-[5-Bromo-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide

To a suspension ofN-(5-bromo-6-pyridin-3-ylpyrazin-2-yl)cyclopropanecarboxamide (4.02 g,12.6 mmol) in CH₂Cl₂ (45 mL), cooled at 0° C., was added mCPBA (3.11 g,12.6 mmol) in small portions. Upon addition completion the ice bath wasremoved and the reaction continued at room temperature for 4 h. Themixture was diluted with CH₂Cl₂ (30 mL) and washed with saturated NaHCO₃(1×25 mL) and saturated NaCl (1×25 mL). The organic layer wasconcentrated in vacuo up to 25 mL volume, and the precipitated productwas filtered and washed with Et₂O (4×5 mL), giving the title compound asa white powder (3.03 g, 72% yield).

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.18 (s, 1H); 8.56 (s, 1H); 8.37 (d, 1H);7.67 (d, 1H); 7.59 (dd, 1H); 2.03 (m, 1H); 11.47 (s, 1H); 0.91 (s, 2H);0.88 (s, 2H).

EM (IE) m/e: 334-336 (M+, 35), 266-268 (62).

Preparation 28

3-Bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

To a 0° C. stirred solution of5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115)(1.10 g, 4.11 mmol) in a mixture of DMSO (13 mL) and water (0.34 mL),was added N-bromosuccinimide (0.77 g, 4.32 mmol) in portions. Afterstirring for 5 h at room temperature, the mixture was poured into water,the precipitate collected by filtration, washed with water and dried togive the title compound as a green solid (0.44 g, 31%).

¹H-NMR (CDCl₃): 8.65 (d, 2H), 8.50 (d, 1H), 8.30 (s, 1H), 7.70 (dd, 1H),7.50 (dd, 1H), 7.20 (m, 1H), 5.45 (s, 2H).

ESI/MS m/e: 345 [M+H]⁺, C₂₁H₁₃FN₆).

Preparation 29 Step a

3-Fluoro-4-methylpyridine

To a cooled (−78° C.) solution of N,N-diisopropylamine (15.92 mL, 113.4mmol) in THF (140 mL) a solution of BuLi 2.5M in hexane (45.4 ml, 113.4mmol) was added dropwise over 30 minutes under an atmosphere of Argon.The mixture was stirred for 30 min. at −78° C. and a solution of3-fluoropyridine (10 g, 103.1 mmol) in THF (5 ml) was added. After 1 hat −78° C., the mixture was treated with MeI (7 ml, 113.4 mmol) and thenwas allowed to reach 25° C. A solution of NaHCO₃ saturated (30 ml) wasadded and the aqueous phase was extracted with diethyl ether. Theorganic layer was dried (MgSO₄) and upon distillation the product wascollected as a colourless liquid, by 130° C., yield 5.3 g (47%)

δ 1H-NMR (CDCl₃): 8.25 (s, 1H), 8.18 (m, 1H), 7.02 (m, 1H).

ESI/MS m/e: 112 ([M+H]+, C₆H₆FN)

Step b

2-(3-fluoropyridin-4-yl)-1-pyridin-3-ylethanone

Obtained (46%) from 3-fluoro-4-methylpyridine and ethylnicotinatefollowing the procedure described in Preparation 11, step a.

δ 1H-NMR (CDCl₃): 9.25 (s, 1H), 8.83 (m, 1H), 8.50 (s, 1H), 8.40 (m,1H), 8.35 (m, 1H), 7.61 (m, 1H), 7.20 (m, 1H), 4.38 (s, 2H).

ESI/MS m/e: 217 ([M+H]+, C₁₂H₉FN₂O)

Step c

1-(3-Fluoropyridin-4-yl)-2-pyridin-3-ylethane-1,2-dione

Obtained (57%) from 2-(3-fluoropyridin-4-yl)-1-pyridin-3-ylethanonefollowing the procedure described in Preparation 11, step b.

δ 1H-NMR (DMSO-d6): 9.21 (d, 1H), 8.90 (dd, 1H), 8.82 (s, 1H), 8.70 (dd,1H), 8.44 (dd, 1H), 7.94 (dd, 1H), 7.67 (ddd, 1H).

ESI/MS m/e: 231 ([M+H]+, C₁₂H₇FN₂O₂)

Step d

5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl[1,2,5]thiadiazolo[3,4-b]pyrazine

Obtained as a solid (63%) from1-(3-fluoropyridin-4-yl)-2-pyridin-3-ylethane-1,2-dione and1,2,5-thiadiazole-3,4-diamine following the procedure of Preparation 11,step c.

δ 1H-NMR (DMSO-d6): 8.64 (m, 3H), 8.58 (dd, 1H), 7.91 (m, 1H), 7.78 (dd,1H), 7.43 (ddd, 1H).

ESI/MS m/e: 311 ([M+H]+, C₁₄H₇FN₆S)

Preparation 30 Step a

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2(1H)-one

A solution of sodium nitrite (0.248 g, 3.6 mmol) in water (2.5 mL) wasadded dropwise to a stirred, cooled (ice-bath) mixture of5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115)(0.80 g, 3.0 mmol) and 5% aqueous sulphuric acid (18 mL). After 1 hour,the mixture was taken to pH 5-6 with aqueous sodium hydroxide solutionwith external cooling. The mixture was concentrated to low bulk thenextracted with chloroform. The organic layer was dried (MgSO₄) andconcentrated in vacuo to give the title compound (0.793 g, 99%) as awhite solid.

δ 1H-NMR (DMSO-d6): 8.55 (dd, 1H), 8.43 (m, 3H), 8.21 (s, 1H), 7.73 (dd,1H), 7.53 (dd, 1H), 7.34 (ddd, 1H).

ESI/MS m/e: 269 ([M+H]+, C₁₄H₉FN₄O)

Step b

5-Chloro-2-(3-fluoropyridin-4-yl)-3-pyridin-3-ylpyrazine

A suspension of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2(1H)-one(0.79 g, 2.95 mmol) in phosphorus oxychloride (5 mL) was heated toreflux and stirred overnight. The mixture was evaporated and carefullyneutralised with 4% aqueous sodium hydrogen carbonate solution withexternal cooling. The mixture was extracted with ethyl acetate and theorganic layer was washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by silica gel chromatography (CH₂Cl₂ to CH₂Cl₂/MeOH98:2) to give the title compound (0.279 g, 33%) as an off-white solid.

δ 1H-NMR (DMSO-d6): 9.02 (s, 1H), 8.48 (m, 4H), 7.82 (m, 1H), 7.65 (dd,1H), 7.41 (ddd, 1H).

ESI/MS m/e: 287 ([M+H]+, C₁₄H₈ClFN₄)

EXAMPLES

TABLE 2 Ex- am- ple Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

Examples Example 1

6-(3-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 0.3 g, 1.11mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (459 mg,2.23 mmol), dioxane (35 mL) and a 2M aqueous solution of cesiumcarbonate (3.3 mL, 6.66 mmol) were added. The Schlenk tube was subjectedto three cycles of evacuation-backfilling with argon, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex [PdCl₂dppf.DCM] (45 mg, 0.055 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in a 100° C. oil bath. After 20 h, themixture was cooled, partitioned between water and ethyl acetate, theaqueous phase extracted twice with ethyl acetate the organic layerswashed with brine, dried (MgSO₄) and evaporated. Flash chromatography(dichloromethane/methanol 98:2 to dichloromethane/methanol 95:5)provided the title compound as a yellowish solid (178 mg, 60%)

m.p.: 221-222° C.

δ ¹H-NMR (CDCl₃): 8.45 (d, 2H), 8.05 (s, 1H), 7.24 (m, 4H), 7.05 (d,2H), 4.86 (s, 2H).

ESI/MS m/e: 267 ([M+H]⁺, C₁₅H₁₁FN₄).

Retention time (min.): 6

Example 2

5-(3-Chloropyridin-4-yl)-6-(3-fluorophenyl)pyrazin-2-amine

A microwave oven reactor was charged with5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 0.3 g, 1.11mmol), (3-chloropyridin-4-yl)boronic acid (212 mg, 1.03 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1:1) (39 mg, 0.047 mmol), dioxane (8 mL) and a1.2M aqueous solution of cesium carbonate was added (1.9 mL, 2.39 mmol).The mixture was heated to 150° C. for 10 min in the microwave oven, thencooled, partitioned between water and ethyl acetate, the aqueous phaseextracted twice with ethyl acetate, the organic layers washed withbrine, dried (MgSO₄) and evaporated. Flash chromatography(dichloromethane to dichloromethane/methanol 90:10) furnished the titlecompound as a yellowish solid (78 mg, 39%).

δ 1H-NMR (CDCl₃): 8.55 (s, 1H), 8.45 (d, 1H), 8.05 (s, 1H), 7.30 (d,1H), 7.15 (m, 2H), 7.00 (m, 2H), 4.85 (bs, 2H).

ESI/MS m/e: 301 ([M+H]⁺, C₁₅H₁₀ClFN₄)

Retention time (min.): 12

Example 3

6-(3-Fluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-amine

Obtained as a brown solid (24%) from5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1) and(3-fluoropyridin-4-yl)boronic acid following the procedure of Example 2.

ESI/MS m/e: 285 ([M+H]⁺, C₁₅H₁₀F₂N₄).

Retention time (min.): 11

Example 4

6-(3-Fluorophenyl)-5-(1,3-thiazol-5-yl)pyrazin-2-amine

A mixture of 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1,100 mg, 0.37 mmol), thiazole (0.06 mL, 0.88 mmol) and potassium acetate(54 mg, 0.56 mmol) in N,N-dimethylacetamide (1 mL) was degassed withargon. The catalyst Pd(PPh₃)₄ (23 mg, 0.02 mmol, 5 mol %) was added anddegassing was repeated. The mixture was heated to 150° C. in a sealedtube and stirred overnight. The mixture was cooled and ethyl acetate andaqueous NH₄Cl were added. The aqueous layer was extracted with ethylacetate. The organic layer was dried and concentrated. The residue waspurified by flash silica gel chromatography (hexanes/EtOAc 1:1) to givethe title compound (15 mg, 15%) as a yellow solid.

ESI/MS (m/e, %): 273 [(M+1)⁺, 100]

Retention time (min.): 11

Example 5

6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-amine

Obtained as a yellowish solid (68%) from5-bromo-6-furan-2-ylpyrazin-2-ylamine (Preparation 2) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine following theprocedure of Example 1.

δ ¹H-NMR (DMSO-d₆): 8.61 (d, 2H), 8.00 (s, 1H), 7.40 (d, 2H), 7.38 (d,1H), 6.58 (d, 1H), 6.40 (m, 1H), 4.85 (s, 1H).

ESI/MS m/e: 239 ([M+H]⁺, C₁₃H₁₀N₄O).

Retention time (min.): 5

Example 6

6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-amine

A microwave oven reactor was charged with5-bromo-6-furan-2-ylpyrazin-2-ylamine (Preparation 2, 220 mg, 0.91mmol), 2-methylsulfanyl-4-trimethylstannanylpyrimidine* (500 mg, 1.74mmol), bis-(triphenylphosphin)palladium (II) chloride (60 mg, 0.08 mmol)and dimethylformamide (2.5 mL). The mixture was heated at 150° C. for 10min in the microwave oven, then cooled, partitioned between water andethyl acetate, the aqueous phase extracted twice with ethyl acetate, theorganic layers washed with brine, dried (MgSO₄) and evaporated. Flashchromatography (dichloromethane to dichloromethane/methanol 95:5) gavethe title compound as a yellowish solid (123 mg, 47%). * Preparedaccording to Sandosham J.; Undheim, K. Tetrahedron 1994, 50 (1),275-284.

ESI/MS m/e: 286 ([M+H]⁺, C₁₃H₁₁N₆OS).

Retention time (min.): 11

Example 7

5-Pyridin-4-yl-6-(2-thienyl)pyrazin-2-amine

Obtained as a brown solid (91%) from5-bromo-6-thiophen-2-ylpyrazin-2-ylamine (Preparation 3) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following theprocedure of Example 1.

ESI/MS m/e: 255 ([M+H]⁺, C₁₃H₁₀N₄S).

Retention time (min.): 6

Example 8

6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-amine

A solution of 1-[5-amino-3-(2-furyl)pyrazin-2-yl]ethanone (Preparation4, 388 mg, 1.91 mmol) in N,N-dimethylformamide dimethyl acetal (1.3 mL)was heated to 100° C. After 9 h, the mixture was concentrated underreduced pressure to yield brown oil. Formamidine acetate (795 mg, 7.64mmol) was added to this oily residue previously dissolved in ethanol(6.4 mL) and toluene (0.96 mL). Molecular sieves (4 Å) were added to thesolution and the whole reaction mixture was heated to 115° C. in asealed tube and stirred for 20 h. The crude reaction was filtered andconcentrated to dryness. The residue was partitioned between ethylacetate and water, the organic layer was washed with brine, dried(Na₂SO₄) and evaporated. The residue was purified by silica gel flashchromatography (100% ethyl acetate). Concentration in vacuo of theproduct-rich fractions provided the titled compound as a pale-yellowsolid (137 mg, 30%).

ESI/MS m/e: 240 ([M+H]⁺, C₁₂H₉N₅O).

Retention time (min.): 7

Example 9

6-(2-Furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-amine

Obtained as a pale-yellow solid (20%) using acetamidine hydrochloridefollowing the procedure of Example 8.

ESI/MS m/e: 254 ([M+H]⁺, C₁₃H₁₁N₅O).

Retention time (min.): 8

Example 10

5-(2-Cyclopropylpyrimidin-4-yl)-6-(2-furyl)pyrazin-2-amine

Obtained as a pale-yellow solid (30%) using cyclopropanecarboximidamidehydrochloride following the procedure of Example 8.

ESI/MS m/e: 280 ([M+H]⁺, C₁₆H₁₃N₅O).

Retention time (min.): 11

Example 11

6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-amine

Obtained as a pale-yellow solid (79%) using benzamidine hydrochloridefollowing the procedure of Example 8.

ESI/MS m/e: 316 ([M+H]⁺, C₁₅H₁₃N₅O).

Retention time (min.): 14

Example 12

6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine

Obtained as a brown solid (39%) from5-bromo-6-pyridin-2-ylpyrazin-2-amine (Preparation 5) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following theprocedure of Example 1.

δ ¹H-NMR (CDCl₃): 8.65 (d, 1H), 8.50 (d, 2H), 8.15 (s, 1H), 7.65 (dd,1H), 7.45 (d, 1H), 7.30 (m, 1H), 7.25 (d, 2H), 4.90 (bs, 2H).

ESI/MS m/e: 250 ([M+H]⁺, C₁₄H₁₁N₅).

Retention time (min.): 4

Example 13

6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine

A mixture of 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.4g, 1.59 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.424 g, 2.07 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1:1) (76 mg, 0.095 mmol) and cesium carbonate(1.55 g, 4.77 mmol) in dioxane (14 mL) and water (3.72 mL) was heated to150° for 10 minutes in the microwave oven. The mixture was partitionedbetween ethyl acetate and water. The organic layer was dried (MgSO₄) andevaporated. Silica gel flash chromatography (95:5dichloromethane/methanol) gave the title compound (0.37 g, 74%) as asolid.

δ ¹H NMR (CDCl₃): 8.68 (dd, 1H), 8.61 (dd, 1H), 8.53 (d, 2H), 8.11 (s,1H), 7.69 (dd, 1H), 7.26 (m, 3H), 4.93 (s, 2H).

ESI/MS (m/e, %): 249 [(M+1)⁺, C₁₄H₁₁N₅]

Example 14

5,6-Dipyridin-4-ylpyrazin-2-amine

Obtained as a green solid (55%) from6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following theprocedure of Example 1.

δ ¹H-NMR (CDCl₃): 8.50 (d, 2H), 8.40 (d, 2H), 8.05 (s, 1H), 7.30 (d,2H), 7.20 (d, 2H), 7.00 (s, 2H).

ESI/MS m/e: 250 ([M+H]⁺, C₄H₁₁N₅).

Retention time (min.): 4

Example 15

N-[6-(5-Methyl-2-furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamideStep a 6-(5-Methylfuran-2-yl)-5-phenylpyrazin-2-ylamine

An oven dried resealable Schlenk tube was charged with6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7, 300 mg, 1.45mmol), 2-methylfuran (1.31 mL, 14.5 mmol), potassium acetate (213 mg,2.17 mmol) and N,N-dimethylacetamide (6 mL). The Schlenk tube wassubjected to three cycles of evacuation-backfilling with argon, andtetrakis(triphenylphosphine)palladium (117 mg, 0.10 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in a 150° C. oil bath. After 40 h, themixture was cooled, partitioned between water and ethyl acetate, theaqueous phase extracted with ethyl acetate (×3), the organic layerswashed with brine, dried (MgSO₄) and evaporated. Flash chromatography(dichloromethane/methanol 98:2 to dichloromethane/methanol 90:10)furnished the title compound as a brown solid (45 mg, 12%).

δ ¹H-NMR (CDCl₃): 8.60 (d, 2H), 7.95 (s, 1H), 7.40 (d, 2H), 6.40 (d,1H), 6.00 (d, 1H), 4.80 (bs, 2H), 2.25 (s, 3H).

Step bN-[6-(5-methyl-2-furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

To a stirred solution of6-(5-methylfuran-2-yl)-5-phenylpyrazin-2-ylamine (42 mg, 0.166 mmol) inpyridine (1.8 mL) was added cyclopropanecarbonyl chloride (38 μL, 0.41mmol). The solution was stirred at 70° C. for 6 h, evaporated,partitioned between dichloromethane and a 4% sodium bicarbonate aqueoussolution, the aqueous phase extracted twice with dichloromethane, theorganic layers washed with brine, dried (MgSO₄) and evaporated. Theresidue was triturated with diethyl ether and methanol and theprecipitate was collected by filtration and dried to furnish the titlecompound as a brown solid (43 mg, 81%).

¹H-NMR (CDCl₃): 9.40 (s, 1H), 8.65 (d, 2H), 8.25 (s, 1H), 7.45 (d, 2H),6.45 (d, 1H), 6.05 (d, 1H), 2.25 (s, 3H), 4.65 (m, 1H), 1.20 (m, 2H),0.95 (m, 2H).

ESI/MS m/e: 321 ([M+H]⁺, C₁₈H₁₆N₄O₂).

Retention time (min.): 11

Example 16

6-(2-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine

Obtained as a white solid (56%) from6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7) and2-fluorophenylboronic acid following the procedure of Example 1.

¹H-NMR (CDCl₃): 8.45 (d, 2H), 8.05 (s, 1H), 7.40 (m, 2H), 7.20 (m, 4H),7.00 (dd, 1H), 4.90 (bs, 2H).

ESI/MS m/e: 267 ([M+H]⁺, C₁₅H₁₁FN₄).

Retention time (min.): 6

Example 17

N-[6-(3-Fluoropyridin-4-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a yellow solid (34%) fromN-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide(Preparation 8) and3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine*following the procedure of Example 1. *Prepared according to Bouillon A.et al. Tetrahedron 2002, 58, 4369-4373.

¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.55 (m, 3H), 8.45 (s, 1H), 8.30 (s, 1H),7.45 (m, 1H), 7.30 (d, 2H), 3.45 (s, 1H), 1.60 (m, 1H), 1.20 (m, 2H),1.0 (m, 2H).

ESI/MS m/e: 336 ([M+H]⁺, C₁₈H₁₄FN₅O).

Retention time (min.): 10

Example 18

N-[6-(3-Chloropyridin-4-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a light brown solid (28%) fromN-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide*(Preparation 8) and3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinefollowing the procedure of Example 1. *Prepared according to Bouillon A.et al. Tetrahedron 2002, 58, 4369-4373.

¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.70 (s, 1H), 8.60 (m, 3H), 8.20 (s, 1H),7.30 (d, 2H), 1.65 (m, 1H), 1.20 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 352 ([M+H]⁺, C₁₈H₁₄ClN₅O)

Retention time (min.): 11

Example 19

N-[6-(1,3-Oxazol-5-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamideStep a 5-(Tributylstannyl)-2-(triisopropylsilyl)-1,3-oxazole

tert-BuLi (1.7M, 8.4 mL, 14.3 mmol) was added dropwise over 30 min. to astirred solution of 2-(triisopropylsilyl)-1,3-oxazole* (3 g, 13 mmol) inTHF (75 mL) at −78° C. under argon. The solution was allowed to stir for20 min. at −78° C. and Bu₃SnCl (5.2 mL, 19.5 mmol) was then added over20 min. The reaction mixture was warmed up to room temperature andstirred for an additional 16 h. The reaction was diluted with ethylacetate and washed with water. The organic layer was dried over MgSO₄and concentrated under reduced pressure. The crude product was dissolvedin n-pentane, filtered through Celite and the solvent evaporated to givethe title compound in quantitative yield as a pale-yellow oily residue,which was used without further purification in the next step. *Preparedaccording to Ross A, et al. Tetrahedron Letters 2002, 43, 935.

δ ¹H NMR (CDCl₃): 1.12 (d, 18H), 1.38 (m, 3H), 1.42 (d, 9H), 1.52-1.95(m, 18H) 7.22 (s, 1H).

Step b

A mixture ofN-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide (100 mg,0.36 mmol) and 5-(tributylstannyl)-2-(triisopropylsilyl)-1,3-oxazole(397 mg, 0.73 mmol) in xylene (3 mL) was degassed with argon. Thecatalyst Pd(PPh₃)₄ (25 mg, 0.022 mmol, 6 mol %) was added and degassingwas repeated. The mixture was heated to 90° C. in a sealed tube andstirred overnight. The mixture was cooled and ethyl acetate and HCl 2Nwere added. The aqueous layer was washed with ethyl acetate and thenneutralized with 6N NaOH. The cloudy solution was extracted with CH₂Cl₂.The organic layer was dried and concentrated. The residue was purifiedby flash silica gel chromatography (dichloromethane/methanol 95:5) togive the title compound (36 mg, 35%) as a white solid.

δ ¹H NMR (CDCl₃): 1.04 (m, 2H), 1.21 (m, 2H), 1.64 (m, 1H), 7.45 (d,1H), 7.88 (s, 1H), 8.28 (s, 1H), 8.74 (d, 1H), 9.56 (s, 1H).

ESI/MS (m/e, %): 308 [(M+1)⁺, 100]

Example 20N-[6-(1,3-Oxazol-2-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Step a (1,3-Oxazol-2-yl)zinc chloride

n-Butyllithium (1.6M, 4.9 mL, 7.9 mmol) was added dropwise over 30 min.to a solution of oxazole (0.5 g, 7.2 mmol) in THF (7 mL) stirred at −78°C. under argon maintaining the mixture at a temperature below −55° C.Fused zinc chloride (1.96 g, 14.4 mmol) was added in two portions andthe reaction mixture was warmed to room temperature and stirred for anadditional 16 h. Two layers are formed and further THF (10 mL) was addedto give a homogeneous solution of the zinc reagent. Approximateconcentration. 0.33 M in THF.

Step b

(1,3-Oxazol-2-yl)zinc chloride (0.33M in THF, 9.3 mL, 3.06 mmol) wasadded to a solution ofN-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide(Preparation 8, 280 mg, 1.02 mmol) in THF (2 mL) and the mixture wasdegassed Pd(PPh₃)₄ (118 mg, 0.102 mmol, 10 mol %) was added anddegassing was repeated. The reaction mixture was heated to 90° C. in asealed tube and stirred overnight. The mixture was cooled and more(1,3-oxazol-2-yl)zinc chloride (0.33M, 5.0 mL, 1.65 mmol) and Pd(PPh₃)₄(90 mg, 8 mol %) were added and the mixture was degassed and heated to90° C. overnight. The reaction mixture was cooled and concentrated. Theresidue was purified by flash silica gel chromatography(dichloromethane/methanol 98:2) to give the title compound (80 mg, 26%)as a pale yellow solid.

δ ¹H NMR (DMSO): 0.95 (m, 4H), 1.18 (m, 1H), 1.64 (m, 1H), 7.40 (d, 3H),7.88 (s, 1H), 8.29 (s, 1H), 8.60 (d, 2H), 9.53 (s, 1H).

ESI/MS (m/e, %): 308 [(M+1)⁺, 100]

Example 21

N-[5-(3-Chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamideStep a 5-(3-Chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.3 g, 1.17 mmol),3-cloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.56 g,2.35 mmol), cesium carbonate (1.15 g, 3.525 mmol) in dioxane (10 mL) andwater (2.8 mL). The Schlenk tube was subjected to three cycles ofevacuation-backfilling with argon, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (58 mg, 0.071 mmol) was added. After three newcycles of evacuation-backfilling with argon, the Schlenk tube was cappedand placed in a 90° C. oil bath. After 16 h, the mixture was cooled,partitioned between water and ethyl acetate, the aqueous phase extractedtwice with ethyl acetate, the organic layers washed with brine, dried(MgSO₄) and evaporated. Flash chromatography (95:5dichloromethane/methanol) gave the title compound (0.16 g, 48%) as asolid.

δ ¹H NMR (CDCl₃): 8.61-8.50 (m, 4H), 8.10 (s, 1H), 7.65 (dt, 1H), 7.34(d, 1H), 7.21 (dd, 1H), 4.93 (s, 2H).

ESI/MS (m/e, %): 283 [(M+1)⁺, C₁₄H₁₀ClN₅].

Step b

Title compound of Example 21 was obtained as a white solid (73%) from5-(3-chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine andcyclopropanecarbonyl following the procedure of Example 15, step b.

δ ¹H NMR (CDCl₃): 9.66 (s, 1H), 9.20 (s, 1H), 8.80 (m, 1H), 8.58 (m,2H), 7.56 (dd, 1H), 7.43 (d, 1H), 7.20 (dd, 1H), 1.75 (m, 1H), 1.22 (m,2H), 1.01 (m, 2H).

ESI/MS (m/e, %): 351 [(M+1)⁺, C₁₈H₁₄ClN₅O]

Example 22

N-[5-(3-Chloropyridin-4-yl)-6-pyridin-2-ylpyrazin-2-yl]cyclopropanecarboxamideStep aN-[6-Chloro-5-(3-chloropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a solid (200 mg, 26%) from6-chloro-5-(3-chloropyridin-4-yl)pyrazin-2-amine (Preparation 9, 240 mg,1 mmol) and cyclopropanecarbonyl chloride (136 μL, 1.5 mmol) followingthe procedure of Example 15, step b.

δ ¹H NMR (CDCl₃): 9.55 (s, 1H), 8.73 (s, 1H), 8.62 (d, 1H), 7.38 (d,1H), 1.70 (m, 1H), 1.17 (m, 1H), 1.00 (m, 1H).

ESI/MS (m/e, %): 308 [(M+1)⁺, C₁₃H₁₀Cl₂N₄O]

Step b

An oven dried resealable Schlenk tube was charged withN-[6-chloro-5-(3-chloropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(0.2 g, 0.65 mmol), 2-(tributylstannyl)pyridine (0.38 g, 1.04 mmol) andxylene (4 mL). The Schlenk tube was subjected to three cycles ofevacuation-backfilling with argon, andtetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in a 150° C. oil bath. After 20 h, themixture was cooled, partitioned between water and ethyl acetate, theaqueous phase was extracted twice with ethyl acetate, the organic layerswashed with brine, dried (MgSO₄) and evaporated. Silica gel flashchromatography (98:2 dichloromethane/methanol) furnished the titlecompound of Example 22 as a light brown solid (110 mg, 48%).

δ ¹H NMR (CDCl₃): 9.64 (s, 1H), 8.57 (d, 1H), 8.51 (s, 1H), 8.39 (d,1H), 8.32 (s, 1H), 7.74 (m, 2H), 7.46 (d, 1H), 1.65 (m, 1H), 1.21 (m,2H), 1.01 (m, 2H).

ESI/MS (m/e, %): 351 [(M+1)⁺, C₁₈H₁₄ClN₅O)

Example 23

N-[5-(3-Chloropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a solid (25%) fromN-[6-chloro-5-(3-chloropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Example 22, step a, 0.37 g, 1.21 mmol) and4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following theprocedure of Example 13.

δ ¹H NMR (CDCl₃): 9.66 (s, 1H), 8.59 (m, 4H), 8.34 (s, 1H), 7.40 (d,1H), 7.25 (s, 1H), 1.70 (m, 1H), 1.22 (m, 2H), 1.02 (m, 2H).

ESI/MS (m/e, %): 351 [(M+1)⁺, C₁₈H₁₄ClN₅O]

Example 24

N-[5-(3-Chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2,2-dimethylpropanamide

Obtained as a solid (20 mg, 26%) from5-(3-chloropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 22, stepa, 0.06 g, 0.21 mmol) and 2,2-dimethylpropanoyl chloride (39 JAL, 0.32mmol) following the procedure of Example 15, step b.

δ ¹H NMR (CDCl₃): 8.66 (d, 1H), 8.62-8.56 (m, 2H), 8.17 (s, 1H), 7.66(dt, 1H), 7A2(d, 1H), 7.24 (m, 2H), 1.40 (s, 9H).

SI/MS (m/e, %): 367 [(M+1)⁺, C₁₉H₁₈ClN₅O].

Example 25

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as an off-white solid (70%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and pyridin-3-ylboronic acid following the procedure ofExample 1.

δ ¹H-NMR (CDCl₃): 9.65 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 8.65 (d,1H), 8.55 (d, 1H), 8.35 (s, 1H), 7.60 (m, 2H), 7.20 (m, 1H), 1.80 (m,1H), 1.20 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 336 ([M+H]⁺, C₁₈H₁₄FN₅O).

Retention time (min.): 11

Example 26

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a light green solid (74%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following theprocedure of Example 1.

¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.60 (d, 2H), 8.55 (m, 1H), 8.35 (s, 2H),7.60 (m, 1H), 1.60 (m, 1H), 1.20 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 336 ([M+H]⁺, C₁₈H₁₄FN₅O).

Retention time (min.): 10

Example 27

6-(3-Fluorophenyl)-N-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine (Example 1, 100 mg,0.37 mmol), 3-bromopyridine (43 μL, 0.45 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (17 mg, 0.03 mmol),cesium carbonate (171 mg, 0.52 mmol) and dioxane (2 mL). The Schlenktube was subjected to three cycles of evacuation-backfilling with argon,and tris(dibenzilideneacetone) dipalladium (14 mg, 0.01 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in a 100° C. oil bath. After 20 h, themixture was cooled and water was added. The solid was collected byfiltration, washed with water, diethyl ether and dried, to give thetitle compound as a yellow solid (88 mg, 63%).

ESI/MS m/e: 344 ([M+H]⁺, C₂₀H₁₄FN₅).

Retention time (min.): 8

Example 28

N-[6-(3-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]pyrimidin-5-amine

Obtained as a yellow solid (51%) from6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine (Example 1) and5-bromopyrimidine following the procedure of Example 27.

ESI/MS m/e: 345 ([M+H]⁺, C₁₉H₁₃FN₆).

Retention time (min.): 10

Example 29

N-[6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]acetamida

Obtained as a brown solid (99%) from6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine (Example 1) and acetylchloride following the procedure of Example 15 (step b).

ESI/MS m/e: 309 ([M+H]⁺, C₁₇H₁₃FN₄O).

Retention time (min.): 10

Example 30

N-[6-(2-Fluorophenyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a brown solid (40%) from6-(2-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine (Example 16) andcyclopropanecarbonyl chloride following the procedure of Example 15(step b).

ESI/MS m/e: 335 ([M+H]⁺, C₁₉H₁₅FN₄O).

Retention time (min.): 12

Example 31

6-(2-Furyl)-N-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine

Obtained as a yellow solid (29%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and3-bromopyridine following the procedure of Example 27.

ESI/MS m/e: 316 ([M+H]⁺, C₁₈H₁₃FN₅O).

Retention time (min.): 6

Example 32

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]pyrimidin-5-amine

Obtained as a brown solid from 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine(Example 5) and 5-bromopyrimidine following the procedure of Example 27.

ESI/MS m/e: 317 ([M+H]⁺, C₁₇H₁₂N₆O).

Retention time (min.): 8.0

Example 33

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide

Obtained as a light brown solid (90%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and acetylchloride following the procedure of Example 15 (step b).

ESI/MS m/e: 281 ([M+H]⁺, C₁₅H₁₂N₄O₂).

Retention time (min.): 7

Example 34

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]propanamide

Obtained as a light brown solid (74%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and propionylchloride following the procedure of Example 15 (step b).

ESI/MS m/e: 295 ([M+H]⁺, C₁₆H₁₄N₄O₂).

Retention time (min.): 8

Example 35

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (100%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) andcyclopropanecarbonil chloride following the procedure of Example 15(step b).

¹H-NMR (DMSO-d₆): 11.40 (s, 1H), 9.30 (s, 1H), 8.65 (d, 2H), 7.75 (s,1H), 7.40 (d, 2H), 6.70 (d, 1H), 6.60 (m, 1H), 2.10 (m, 1H), 0.90 (d,4H).

ESI/MS m/e: 307 ([M+H]⁺, C₁₇H₁₄N₄O₂).

Retention time (min.): 13

Example 36

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclobutanecarboxamide

Obtained as a light brown solid (74%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) andcyclobutanecarbonyl chloride following the procedure of Example 15 (stepb).

¹H-NMR (DMSO-d₆): 10.90 (s, 1H), 9.35 (s, 1H), 8.65 (d, 2H), 7.70 (s,1H), 7.40 (d, 2H), 6.70 (d, 1H), 6.60 (m, 1H), 3.50 (m, 1H), 2.25 (m,2H), 2.10 (m, 2H), 2.00 (m, 2H).

ESI/MS m/e: 321 ([M+H]⁺, C₁₈H₁₆N₄O₂).

Retention time (min.): 11

Example 37

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]cyclopentanecarboxamide

Obtained as a light brown solid (61%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) andcyclopentanecarbonyl chloride following the procedure of Example 15(step b).

¹H-NMR (DMSO-d₆): 11.0 (s, 1H), 9.35 (s, 1H), 8.65 (d, 2H), 7.75 (s,1H), 7.40 (d, 2H), 6.70 (d, 1H), 6.60 (m, 1H), 3.00 (m, 1H), 1.90 (m,2H), 1.70 (m, 4H), 1.50 (m, 2H).

ESI/MS m/e: 335 ([M+H]⁺, C₁₉H₁₆N₄O₂).

Retention time (min.): 12

Example 38

N-[6-(2-Furyl)-5-pyridin-4-ylpyrazin-2-yl]-2-methylpropanamide

Obtained as a light brown solid (98%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and isobutirylchloride following the procedure of Example 15 (step b).

ESI/MS m/e: 309 ([M+H]⁺, C₁₇H₁₆N₄O₂).

Retention time (min.): 10

Example 39

2-Cyclopentyl-N-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide

Obtained as a light brown solid (48%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) andcyclopentylacetyl chloride following the procedure of Example 15 (stepb).

ESI/MS m/e: 349 ([M+H]⁺, C₂₀H₂₀N₄O₂).

Retention time (min.): 14

Example 40

4-Fluoro-N-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]benzamide

Obtained as a solid (50 mg, 45%) from6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5) and4-fluorobenzoyl chloride following the procedure of Example 15 (step b).

δ ¹H NMR (CDCl₃): 9.65 (s, 1H), 8.71 (m, 2H), 8.60 (s, 1H), 8.02 (m,2H), 7.46 (m, 2H), 7.26 (m, 2H), 6.63 (d, 1H), 6.47 (m, 1H).

ESI/MS (m/e, %): 360 [(M+1)⁺, C₂₀H₁₃FN₄O₂]

Example 41

N-Cyclopentyl-N′-[6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]urea

To a stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine(Example 5, 90 mg, 0.378 mmol) in pyridine (1 mL) cyclopentylisocianate(42 μL, 0.378 mmol) was added and the solution was refluxed overnight.The residue was purified by silica gel flash column chromatography (98:2dichloromethane/methanol) to give the title compound (58 mg, 44%) as asolid.

δ ¹H NMR (CDCl₃): 9.26 (m, 2H), 8.69 (m, 2H), 8.26 (s, 1H), 7.45 (m,3H), 4.29 (m, 1H), 2.13-1.62 (m, 8H).

ESI/MS (m/e, %): 349 [(M+1)⁺, C₁₉H₁₉N₅O₂]

Example 42

N-{6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-yl}acetamide

Obtained as an off-white solid (53%) from6-(2-furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-amine (Example 6)and acetyl chloride following the same procedure of Example 15 (step b).

ESI/MS m/e: 328 ([M+H]⁺, C₁₅H₁₃N₅O₂S).

Retention time (min.): 12

Example 43

N-{6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-yl}cyclopropanecarboxamide

Obtained as an off-white solid from6-(2-furyl)-5-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-amine (Example 6)and cyclopropanecarbonyl chloride following the same procedure ofExample 15 (step b).

ESI/MS m/e: 354 ([M+H]⁺, C₁₇H₁₅N₅O₂S).

Retention time (min.): 14

Example 44

N-[5-Pyridin-4-yl-6-(2-thienyl)pyrazin-2-yl]acetamida

Obtained as an off-white solid (32%) from5-pyridin-4-yl-6-(2-thienyl)pyrazin-2-amine (Example 7) and acetylchloride following the same procedure of Example 15 (step b).

¹H-NMR (DMSO-d₆): 11.0 (s, 1H), 9.25 (s, 1H), 8.65 (d, 2H), 7.70 (d,1H), 7.50 (d, 2H), 6.70 (dd, 1H), 6.80 (d, 1H), 2.20 (s, 3H).

ESI/MS m/e: 397 ([M+H]⁺, C₁₅H₁₂N₄OS).

Retention time (min.): 9

Example 45

N-[6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-yl]acetamide

Sodium hydride (42 mg, 1.05 mmol) was added to a stirred solution of6-(2-furyl)-5-pyrimidin-4-ylpyrazin-2-amine (Example 8, 100 mg, 0.42mmol) in DMF (4 mL) at 0° C. under nitrogen. The solution was allowed tostir for 30 min. at 0° C. Acetyl chloride (60.0 μL, 0.84 mmol) was thenadded and the reaction mixture was warmed up to room temperature andstirred for 3 days. The reaction was diluted with ethyl acetate andwashed with water. The organic layer was washed with brine, dried(Na₂SO₄) and evaporated. The residue was purified by silica gel flashchromatography (50% ethyl acetate in hexanes to 75% ethyl acetate inhexanes). Concentration in vacuo of the product-rich fractions providedthe titled compound as a pale-yellow solid (8 mg, 7%).

δ ¹H NMR (CD₃OD): 9.40 (s, 1H), 9.15 (s, 1H), 8.90 (d, 1H), 7.90 (d,1H), 7.20 (s, 1H), 7.05 (d, 1H), 6.55 (m, 1H), 3.30 (bs, 1H), 2.25 (s,3H).

ESI/MS m/e: 282 ([M+H]⁺, C₁₄H₁₁N₅O₂).

Retention time (min.): 9

Example 46

N-[6-(2-Furyl)-5-pyrimidin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a pale-yellow solid (7%) using cyclopropanecarbonyl chloridefollowing the procedure of Example 45.

δ ¹H NMR (CDCl₃): 9.50 (s, 1H), 9.15 (s, 1H), 8.90 (d, 1H), 8.45 (bs,1H), 7.70 (d, 1H), 7.35 (s, 1H), 6.80 (d, 1H), 6.50 (m, 1H), 1.65 (m,1H), 1.20 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 308 ([M+H]⁺, C₁₅H₁₃N₃O₂).

Retention time (min.): 11

Example 47

N-[6-(2-Furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Cyclopropanecarbonyl chloride (0.028 mL, 0.30 mmol) was added to astirred solution of6-(2-furyl)-5-(2-methylpyrimidin-4-yl)pyrazin-2-amine (Example 9, 38 mg,0.15 mmol) in pyridine (0.5 mL). The mixture was heated to 80° C. in asealed tube and stirred for 3 h. The crude reaction was concentrated todryness and the residue was diluted with ethyl acetate and washed withaqueous sodium bicarbonate 4%. The organic layer was dried (Na₂SO₄) andevaporated. The residue was purified with flash silica gelchromatography (30% ethyl acetate in hexanes). Concentration in vacuo ofthe product-rich fractions provided the titled compound as a pale-yellowsolid (12 mg, 25%).

ESI/MS m/e: 322 ([M+H]⁺, C₁₇H₁₃N₃O₂).

Retention time (min.): 11

Example 48

N-[5-(2-Cyclopropylpyrimidin-4-yl)-6-(2-furyl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a pale-yellow solid (58%) from5-(2-cyclopropylpyrimidin-4-yl)-6-(2-furyl)pyrazin-2-amine (Example 10)following the procedure of Example 47.

ESI/MS m/e: 348 ([M+H]⁺, C₁₉H₁₇N₃O₂).

Retention time (min.): 13

Example 49

N-[6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-yl]acetamide

Obtained as a pale-yellow solid (17%) from6-(2-furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-amine (Example 11) andacetyl chloride following the procedure of Example 47.

δ ¹H NMR (CDCl₃): 9.50 (s, 1H), 8.95 (d, 1H), 8.25 (m, 2H), 8.10 (bs,1H), 7.75 (d, 1H), 7.50 (m, 3H), 7.40 (bs, 1H), 6.90 (d, 1H), 6.50 (bs,1H), 2.30 (s, 3H).

ESI/MS m/e: 358 ([M+H]⁺, C₂₀H₁₅N₅O₂).

Retention time (min.): 15

Example 50

N-[6-(2-Furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a pale-yellow solid (22%)6-(2-furyl)-5-(2-phenylpyrimidin-4-yl)pyrazin-2-amine (Example 11)following the procedure of Example 47.

δ ¹H NMR (CDCl₃): 9.50 (s, 1H), 8.95 (d, 1H), 8.40 (bs, 1H), 8.25 (m,2H), 7.70 (d, 1H), 7.50 (m, 3H), 7.40 (bs, 1H), 6.85 (d, 1H), 6.45 (bs,1H), 1.70 (m, 1H), 1.20 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 384 ([M+H]⁺, C₂₂H₁₇N₅O₂).

Retention time (min.): 17

Example 51

N-(6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)acetamide

Obtained as a brown solid (56%) from6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12) and acetylchloride following the same procedure of Example 15 (step b).

ESI/MS m/e: 292 ([M+H]⁺, C₁₆H₁₃N₆O).

Retention time (min.): 6

Example 52

N-(6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide

Obtained as a brown solid (44%) from 6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12) and cyclopropanecarbonyl chloride followingthe same procedure of Example 15 (step b).

¹H-NMR (DMSO-d₆): 11.40 (s, 1H), 9.45 (s, 1H), 8.40 (m, 3H), 7.95 (t,1H), 7.50 (d, 2H), 7.80 (d, 1H), 7.25 (m, 1H), 2.05 (m, 1H), 0.95 (d,4H).

ESI/MS m/e: 318 ([M+H]⁺, C₁₈H₁₅N₅O).

Retention time (min.): 8

Example 53

N-Cyclopentyl-N′-(6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)urea

Sodium hydride (17 mg, 0.43 mmol) in anhydrous dimethylformamide (3.5mL) was stirred at 0° C. under nitrogen atmosphere.6-Pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12, 90 mg, 0.36mmol) in anhydrous dimethylformamide (2.5 mL) and cyclopentylisocianate(50 μL, 0.43 mmol) were sequentially added. The mixture was stirred at70° C. under nitrogen atmosphere for 1 h 30 min. Dimethylformamide wasremoved in vacuo and the resulting solid was triturated withhexanes-dichloromethane, filtered, washed with hexanes and dried. Silicagel flash chromatography of the solid (dichloromethane todichloromethane/methanol 95:5) afforded the title compound (53 mg, 41%)as a white solid.

ESI/MS m/e: 361 ([M+H]⁺, C₂₀H₂₀N₆O).

Retention time (min.): 10

Example 54

N-(4-Fluorophenyl)-N′-(6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-yl)urea

Obtained as a light yellow solid (37%) from6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12) and4-fluorophenylisocianate following the same procedure of Example 53.

¹H-NMR (CDCl₃): 11.50 (s, 1H), 9.55 (s, 1H), 8.75 (d, 1H), 8.55 (d, 2H),7.80 (t, 1H), 7.45 (m, 3H), 7.30 (m, 4H), 7.05 (t, 2H)

ESI/MS m/e: 387 ([M+H]⁺, C₂₁H₁₅FN₆O).

Retention time (min.): 12

Example 55

N-(6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide

Obtained as a solid (90%) from6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13) andcyclopropanecarbonyl chloride following the procedure of Example 15(step b).

δ ¹H NMR (CDCl₃): 9.62 (s, 1H), 8.77 (m, 1H), 8.64 (d, 1H), 8.58 (m,2H), 8.65 (m, 1H), 7.33 (m, 2H), 7.26 (m, 1H), 1.72 (m, 1H), 1.22 (m,2H), 1.01 (m, 1H).

ESI/MS (m/e, %): 317 [(M+1)⁺, C₁₈H₁₅N₅O]

Example 56

N-(6-Pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)cyclobutanecarboxamide

Obtained as a white solid (57%) from6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13) andcyclobutanecarbonyl chloride following the same procedure of Example 15(step b).

¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.75 (s, 1H), 8.60 (d, 1H), 8.75 (d, 2H),7.95 (s, 1H), 7.65 (d, 1H), 7.30 (d, 2H), 7.20 (s, 1H), 3.30 (m, 1H),2.45 (m, 4H), 2.00 (m, 2H).

ESI/MS m/e: 332 ([M+H]⁺, C₁₉H₁₇N₅O).

Retention time (min.): 9

Example 57

N-cyclopentyl-N′(6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)urea

Obtained as a white solid (90%) from6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13) andcyclopentylisocianate following the same procedure of Example 53.

δ ¹H NMR (CDCl₃): 9.06 (s, 1H), 8.91 (d, 1H), 8.74 (m, 1H), 8.68 (m,1H), 8.57 (d, 1H), 8.42 (s, 1H), 7.66 (m 1H), 7.32 (m, 2H), 4.27 (m,1H), 2.08-1.47 (m, 8H).

ESI/MS (m/e, %): 360 [(M+1)⁺, C₂₀H₂₀N₆O].

Example 58

N-(4-fluorophenyl)-N′-(6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-yl)urea

Obtained as a solid (32%) from6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13) and1-fluoro-4-isocyanatobenzene following the procedure of Example 53.

δ ¹H NMR (CDCl₃): 8.80 (m, 1H), 8.69 (m, 2H), 8.56 (d, 2H), 7.70 (d,1H), 7.45 (dd, 2H), 7.35 (m, 3H), 7.05 (t, 2H).

ESI/MS (m/e, %): 386 [(M+1)⁺, C₂₁H₁₅FN₆O]

Example 59

6-Pyridin-3-yl-5-pyridin-4-yl-N-1,3-thiazol-2-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13, 60 mg, 0.241mmol), 2-bromo-1,3-thiazole (22 μL, 0.241 mmol), cesium carbonate (110mg, 0.337 mmol) and dioxane (2.5 mL). The Schlenk tube was subjected tothree cycles of evacuation-backfilling with argon, andtris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.01 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 0.019 mmol) wasadded. After three new cycles of evacuation-backfilling with argon, theSchlenk tube was capped and placed in a 100° C. oil bath. After 16 h,the mixture was cooled, partitioned between water and ethyl acetate, theaqueous phase was extracted twice with ethyl acetate, the organic layerswashed with brine, dried (MgSO₄) and evaporated. Flash chromatography(95:5 dichloromethane/methanol) furnished the title compound as a solid(35 mg, 44%).

δ ¹H NMR (CDCl₃): 8.96 (m, 1H), 8.69 (d, 1H), 8.60 (d, 2H), 8.52 (s,1H), 7.85 (d, 1H), 7.58 (d, 1H), 7.39 (m, 2H), 7.26 (s, 1H), 7.00 (d,1H).

ESI/MS (m/e, %): 332 [(M+1)⁺, C₁₇H₁₂N₆S]

Example 60

N-(5,6-Dipyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide

Obtained as an off-white solid (48%) from5,6-dipyridin-4-ylpyrazin-2-amine (Example 14) and cyclopropanecarbonylchloride following the same procedure of Example 15 (step b).

¹H-NMR (DMSO-d₆): 11.45 (s, 2H), 9.45 (s, 1H), 8.60 (d, 2H), 8.55 (d,2H), 7.35 (d, 2H), 7.30 (d, 2H), 2.10 (m, 1H), 0.95 (d, 4H).

ESI/MS m/e: 318 ([M+H]⁺, C₁₈H₁₅N₅O).

Retention time (min.): 7

Example 61

3-Bromo-6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-amine

To a solution of 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-ylamine(Example 1, 70 mg, 0.26 mmol) in chloroform (4 mL) at 0° C. was addedpyridine (22 μL, 0.27 mmol) and bromine (14 μL, 0.27 mmol). The reactionmixture was stirred at room temperature for 24 h, chloroform (20 mL) wasadded, the organic layer was washed with water and brine, dried (MgSO₄)and evaporated. The residue was purified by silica gel flash columnchromatography (dichloromethane/methanol 95:5) to provide the titlecompound as a red solid (22 mg, 24%).

ESI/MS m/e: 345 ([M+H]⁺, C₁₅H₁₀BrFN₄).

Retention time (min.): 9

Example 62

3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

To a 0° C. stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine(Example 5, 195 mg, 0.82 mmol) in dimethylsulfoxide (1.5 mL) and water(40 μL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol).The mixture was stirred at room temperature for 40 min, then poured intowater, extracted with dichloromethane (×3), the organic layers washedwith brine, dried (MgSO₄) and evaporated to furnish the title compound(198 mg, 75%) as a brown solid.

¹H-NMR (DMSO-d₆): 8.55 (d, 2H), 7.65 (s, 1H), 7.25 (d, 2H), 7.10 (s,2H), 6.65 (d, 2H), 6.55 (d, 2H).

ESI/MS m/e: 318 ([M+H]⁺, C₁₃H₉BrN₄O).

Retention time (min.): 7

Example 63

3-Bromo-6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine

Obtained as a brown solid (30%) from6-pyridin-3-yl-5-pyridin-4-ylpyrazin-2-amine (Example 13) andN-bromosuccinimide following the same procedure of Example 62.

ESI/MS m/e: 329 ([M+H]⁺, C₁₄H₁₀BrN₅).

Retention time (min.): 6

Example 64

3-Amino-5-(2-furyl)-6-pyridin-4-ylpyrazine-2-carbonitrile

A mixture of sodium cyanide (21 mg, 0.42 mmol) and copper (I) cyanide(38 mg, 0.42 mmol) in anhydrous dimethylformamide (1.5 mL) was heated to120° C. 3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62,90 mg, 0.28 mmol) was added in portions. After stirring at 120° C. fortwo hours, the mixture was cooled and evaporated. A 0.75M aqueoussolution of sodium cyanide (6 mL) was added, stirred for 10 min at roomtemperature and partitioned between water and ethyl acetate. The aqueousphase was extracted twice with ethyl acetate, the organic layers washedwith brine, dried (MgSO₄), and evaporated. Silica gel flash columnchromatography (dichloromethane/methanol 98:2) furnished the titlecompound as a dark yellow solid (52 mg, 70%).

¹H-NMR (DMSO-d₃): 8.60 (d, 2H), 7.75 (s, 1H), 7.65 (bs, 2H), 7.35 (m,2H), 6.75 (s, 1H), 6.60 (m, 1H).

ESI/MS m/e: 264 ([M+H]⁺, C₁₄H₉N₅O)

Retention time (min.): 7

Example 65

3-Ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine Step a6-(2-Furyl)-5-Pyridin-3-trimethylsilyl-4-ylpyrazin-2-amine

An oven dried resealable Schlenk tube was charged with3-bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 90 mg,0.28 mmol), trimethylsilylacetilene (80 μL, 0.56 mmol) andtetrahydrofuran (1 mL). The Schlenk tube was subjected to three cyclesof evacuation-backfilling with argon, andtetrakis(triphenylphosphine)palladium (8 mg, 0.01 mmol) and copper (I)iodide (2.2 mg, 0.01 mmol) were added. After three new cycles ofevacuation-backfilling with argon, the Schlenk tube was capped andplaced in a 90° C. oil bath. After 3 h, the mixture was cooled,partitioned between water and ethyl acetate, the aqueous phase extractedtwice with ethyl acetate, the organic layers washed with brine, dried(MgSO₄) and evaporated. Silica gel flash chromatography(dichloromethane/methanol 90:10) furnished the title compound as aorange oil (48 mg, 51%).

Step b 3-Ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

A mixture of 6-(2-furyl)-5-pyridin-3-trimethylsilyl-4-ylpyrazin-2-amine(45 mg, 0.13 mmol) and potassium carbonate (28 mg, 0.20 mmol) inmethanol (2 mL) was stirred at room temperature for 3 h. The mixture waspartitioned between water and ethyl acetate, the aqueous phase extractedtwice with ethyl acetate, the organic layers washed with brine, dried(MgSO₄) and evaporated to give the title compound (28 mg, 80%) as abrown solid.

¹H-NMR (CDCl₃): 8.60 (d, 2H), 7.45 (s, 1H), 7.40 (d, 2H), 6.55 (d, 1H),6.45 (d, 1H), 5.5 (bs, 2H), 3.60 (s, 1H).

ESI/MS m/e: 263 ([M+H]⁺, C₁₅H₁₀N₄O).

Retention time (min.): 6

Example 66

6-(2-Furyl)-3-(phenylethynyl)-5-pyridin-4-ylpyrazin-2-amine

Obtained as a brown solid (54%)3-bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62) andphenylacetylene following the same procedure of Example 65 (Step a).

ESI/MS m/e: 339 ([M+H]⁺, C₂₁H₁₄N₄O)

Retention time (min.): 12

Example 67

6-(2-Furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-amine

3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 160 mg,0.5 mmol) was suspended in methanol (5 mL), sodium methoxide was added(0.12 mL, solution 30% in methanol, 0.5 mmol) and the solution washeated to 70° C. for 2 hours. The mixture was cooled, the solvent wasevaporated in vacuo and the residue was partitioned betweendichloromethane and brine. The aqueous layer was extracted withdichloromethane. The organic layer was dried and concentrated. Theresidue was triturated with diethyl ether to provide the target compoundas a brownish solid (62 mg, 46%)

δ ¹H NMR (CDCl₃): 4.08 (s, 3H), 5.03 (bs, 2H), 6.42 (s, 1H), 7.23 (s,1H), 7.38 (m, 3H), 8.59 (d, 2H)

ESI/MS (m/e, %): 269 [(M+1)⁺, 100]

Retention time (min.): 6

Example 68

3-Ethyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

To a solution of 3-ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine(Example 65, 50 mg, 0.19 mmol) in ethanol (4 mL) was added platinumdioxide (5 mg). The mixture was hydrogenated at 1 atmosphere and at roomtemperature for 18 h, filtered, washed with methanol and dichloromethaneand evaporated to give the title compound as a white solid (44 mg, 88%).

ESI/MS m/e: 267 ([M+H]⁺, C₁₅H₁₄N₄O).

Retention time (min.): 12

Example 69

N-[3-Cyano-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide

Obtained as a yellow solid (45%) from3-amino-5-(2-furyl)-6-pyridin-4-ylpyrazine-2-carbonitrile (Example 64)and acetyl chloride following the same procedure of Example 15 (step b).

ESI/MS m/e: 306 ([M+H]⁺, C₁₆H₁₁N₅O₂).

Retention time (min.): 8

Example 70

N-[6-(2-Furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a yellow solid (70%) from6-(2-furyl)-3-methoxy-5-pyridin-4-ylpyrazin-2-amine (Example 67) andcyclopropanecarbonyl chloride following the same procedure of Example 15(step b).

¹H-NMR (CDCl₃): 1.25 (m, 5H), 4.08 (s, 3H), 6.42 (m, 1H), 7.31 (s, 1H),7.40 (m, 3H), 8.20 (bs, 1H), 8.70 (d, 2H)

ESI/MS m/e: 337 ([M+H]⁺, C₁₈H₁₆N₄O₃)

Retention time (min.): 8

Example 71

N-[3-ethyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-yl]acetamide

Obtained as a yellow solid (45%) from3-ethyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 68) andacetyl chloride following the same procedure of Example 15 (step b).

ESI/MS m/e: 308 ([M+H]⁺, C₁₈H₁₆N₄O₂).

Retention time (min.): 8

Example 72

5-(3-Fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine

A mixture of5-(3-fluorophenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 11) (1.6 g, 5.2 mmol) in ammonia solution (32%, 30 mL) wasstirred and heated under reflux for 1 h. The reaction was allowed tocool to room temperature, diluted with water and the suspension obtainedwas filtered to provide the title compound as a brown solid (0.7 g,48%).

δ ¹H-NMR (DMSO-d₆): 8.39 (d, J=6.0 Hz, 2H), 7.26 (m, 1H), 7.19 (d, J=6.0Hz, 2H), 7.11-6.99 (m, 3H), 6.42 (s, 2H), 6.35 (s, 2H).

ESI/MS m/e: 282 ([M+H]+, C₁₅H₁₂FN₅)

Retention time (min.): 7

Example 73

3-Amino-5-(3-fluorophenyl)-6-pyridin-4-ylpyrazin-2-ol

To a cooled solution (0° C.) of5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 100mg, 0.36 mmol) in HCl 1N (1 mL) was added dropwise a solution of sodiumnitrite (35 mg, 0.50 mmol) in water (0.6 mL). The reaction was stirredfor 1 h at room temperature and after this period was driven to pH7 byaddition of a NaHCO₃ 4% solution. The suspension was filtered to leave asolid which was purified by silica gel chromatography eluting withCH₂Cl₂/MeOH/NH₃ (50:8:1) to afford the title compound (37 mg, 36%).

δ ¹H-NMR (DMSO-d₆): 12.05 (s, 1H), 8.48 (d, J=5.4 Hz, 2H), 7.24 (m, 1H),7.18 (d, 2H), 7.07-6.90 (m, 4H).

ESI/MS m/e: 283 ([M+H]⁺, C₁₅H₁₁FN₄O)

Retention time (min.): 8

Example 74

6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 72, 300 mg, 1.07 mmol) in1,1′,1″-[methanetriyltris(oxy)]triethane (3 mL) was stirred and heatedat 140° C. overnight. The solvent was removed under vacuum and theresidue was triturated with diethyl ether. The resulting solid waspurified by silica gel column chromatography (CH₂Cl₂/MeOH 9:1) to affordthe title compound as a yellow solid (136 mg, 44%)

δ ¹H-NMR (DMSO-d₈): 13.78 (s, 1H), 8.94 (s, 1H), 8.55 (d, J=6.0 Hz, 2H),7.42-7.36 (m+d, 3H), 7.23-7.16 (m, 3H).

ESI/MS m/e: 292 ([M+H]+, C₁₆H₁₀FN₅)

Retention time (min.): 8

Example 75

6-(3-Fluorophenyl)-2-methyl-5-pyridin-4-yl-1H-Imidazo[4,5-b]pyrazine

A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 72, 300 mg, 1.07 mmol) in acetic anhydride (3 mL) was stirredand heated at 140° C. for 4 h. Then polyphosphoric acid was added (0.32g) and allowed to react at the same temperature for 2 h. Upon cooling,water was added and the product extracted with ethyl acetate. The crudeobtained was purified by silica column chromatography eluting with agradient from CH₂Cl₂ to CH₂Cl₂/MeOH 95:5 to afford the title compound asa yellow solid (36 mg, 52%).

δ ¹H-NMR (DMSO-d₈): 13.34 (s, 1H), 8.39 (d, J=3.9 Hz, 2H), 7.25-7.20(m+d, 3H), 7.10-7.00 (m, 3H).

ESI/MS m/e: 306 ([M+H]⁺, C₁₇H₁₂FN₅)

Retention time (min.): 8

Example 76

5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 72, 200 mg, 0.71 mmol), 1,1′-carbonylbis-1H-imidazole (138 mg,0.85 mmol) in THF (3 mL) was stirred and heated at reflux overnight.Solvent was removed under reduced pressure and the residue waspartitioned between water and ethyl acetate. The separated organic phasewas dried (MgSO₄) and evaporated to dryness. The residue wasrecrystallized from ethanol to give the title compound as a white solid(96 mg, 44%).

δ ¹H-NMR (DMSO-d₆): 12.03 (s, 2H), 8.50 (d, J=6.0 Hz, 2H), 7.35 (m, 1H),7.27 (d, J=6.0 Hz, 2H), 7.18-7.07 (m, 3H).

ESI/MS m/e: 308 ([M+H]⁺, C₁₆H₁₀FN₅O)

Retention time (min.): 8

Example 77

6-(3-Fluorophenyl)-5-pyridin-4-yl-2-(trifluoromethyl)-1H-Imidazo[4,5-b]pyrazine

A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 72, 100 mg, 0.36 mmol) in trifluoroacetic anhydride (3 mL) wasstirred and heated at 120° C. for 3 h. Then polyphosphoric acid wasadded (100 mg) and allowed to react at the same temperature for 2 h.Upon cooling, an aqueous solution of NaHCO₃ 4% was added and the crudeproduct extracted with ethyl acetate. The organic phase was dried(MgSO₄), concentrated and the residue was purified by silica columnchromatography (CH₂Cl₂/MeOH 95:5) to provide the title compound as abrown solid (58 mg, 45%).

δ ¹H-NMR (DMSO-d₆): 8.62 (d, 2H), 7.63 (d, 2H), 7.42-7.20 (m, 4H). (200)

ESI/MS m/e: 360 ([M+H]⁺, C₁₇H₆F₄N₆)

Retention time (min.): 12

Example 78

5-Phenyl-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (51%) from5-phenyl-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine (Preparation12) following the procedure described in Example 72.

δ 1H-NMR (DMSO-d₆): 8.37 (d, 2H), 7.28 (brs, 5H), 7.19 (d, 2H), 6.37 (s,2H), 6.21 (s, 2H).

ESI/MS m/e: 264 ([M+H]+, C₁₅H₁₃N₅)

Retention time (min.): 5

Example 79

5-(4-Fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (69%) from5-(4-fluorophenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 13) following the procedure described in Example 72.

δ 1H-NMR (DMSO-d₆): 8.38 (d, 2H), 7.28-7.23 (m, 2H), 7.17 (d, 2H), 7.10(t, 2H), 6.40 (s, 2H), 6.28 (s, 2H).

ESI/MS m/e: 282 ([M+H]+, C₁₅H₁₂FN₅)

Retention time (min.): 6

Example 80

5-(3-Methylphenyl)-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (81%) from5-(3-methylphenyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 14) following the procedure described in Example 72.

δ 1H-NMR (DMSO-d₆): 8.37 (d, 2H), 7.18 (d, 2H), 7.17-7.04 (m, 3H), 6.94(brd, 1H), 2.23 (s, 3H).

ESI/MS m/e: 278 ([M+H]+, C₁₆H₁₅N₅)

Retention time (min.): 7

Example 81

5-(2-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine

Obtained (52%) from5-(2-fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 15) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d₆): 8.51 (d, 1H), 7.44 (d, 1H), 7.40 (t, 1H), 7.30 (m,1H), 7.20 (t, 1H), 7.04 (t, 1H), 1.71 (s, 3H).

ESI/MS m/e: 345 ([M+H]+, C₁₅H₁₃FN₆S)

Retention time (min.): 12

Example 82

6-(2-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine

Obtained (64%) from5-(2-fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine(Example 81) following the procedure described in Example 74.

ESI/MS m/e: 339 ([M+H]+, C₁₆H₁₁FN₆S)

Retention time (min.): 12

Example 83

5-(3-Chlorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine

Obtained (52%) from5-(3-chlorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 16) following the procedure described in Example 72.

ESI/MS m/e: 345 ([M+H]+, C₁₅H₁₃ClN₆S)

Retention time (min.): 14

Example 84

6-(3-Chlorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine

Obtained (66%) from5-(3-chlorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine(Example 83) following the procedure described in Example 74.

ESI/MS m/e: 355 ([M+H]+, C₁₆H₁₁ClN₆S)

Retention time (min.): 14

Example 85

5-(3-Fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine

Obtained (73%) from5-(3-fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 17) following the procedure described in Example 72.

δ 1H-NMR (DMSO-d₆): 8.53 (d, 1H), 7.44 (d, 1H), 7.25 (m, 1H), 7.03 (m,3H), 6.65 (s, 2H), 6.38 (s, 2H).

ESI/MS m/e: 329 ([M+H]⁺, C₁₅H₃FN₆S)

Retention time (min.): 13

Example 86

6-(3-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine

Obtained (53%) from5-(3-fluorophenyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine(Example 85) following the procedure described in Example 74.

δ ¹H-NMR (DMSO-d₆): 8.80 (s, 1H), 8.58 (d, 1H), 7.39-7.05 (m, 5H)

ESI/MS m/e: 339 ([M+H]+, C₁₆H₁₁FN₆S)

Retention time (min.): 13

Example 87

5-(2-Furyl)-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (92%) from5-(2-furyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine (Preparation18) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d₆): 8.46 (d, 2H), 7.49 (s, 1H), 7.18 (d, 2H), 6.49-6.36(m, 6H).

ESI/MS m/e: 254 ([M+H]+, C₁₃H₁₁N₅O)

Retention time (min.): 5

Example 88

3-Amino-5-(2-furyl)-6-pyridin-4-ylpyrazin-2-ol

Obtained (25%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) following the procedure described in Example 73.

ESI/MS m/e: 255 ([M+H]+, C₁₃H₁₀N₄O₂)

Retention time (min.): 5

Example 89

6-(2-Furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (30%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) following the procedure described in Example 74.

δ ¹H-NMR (DMSO-d₆): 13.73 (brs, 1H), 8.92 (s, 1H), 8.65 (d, J=6.3 Hz,2H), 7.67 (s, 1H), 7.42 (d, J=6.3 Hz, 2H), 6.65 (s, 1H), 6.59 (s, 1H).

ESI/MS m/e: 264 ([M+H]+, C₁₄H₉N₅O)

Retention time (min.): 6

Example 90

6-(2-Furyl)-2-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

A mixture of 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 87,146 mg, 0.58 mmol) and nicotinoyl chloride hydrochloride (516 mg, 2.9mmol) in pyridine (5 mL) was stirred and heated at reflux for 24 h. Thenpolyphosphoric acid was added and the stirring was continued at the sametemperature for 24 h. The reaction was allowed to cool to roomtemperature and was poured into water and extracted with ethyl acetate.The organic phase was dried (MgSO₄), evaporated and the residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH/NH₃ 50:8:1). Theappropriate fractions were concentrated to leave a solid which uponwashing with diethyl ether give the title compound as a light brownsolid (82 mg, 61%).

δ ¹H-NMR (DMSO-d₆): 9.47 (s, 1H), 8.79 (d, J=3.9 Hz, 1H), 8.67-8.62 (m,3H), 7.70-7.66 (m, 2H), 7.44 (d, J=5.7 Hz, 1H), 6.71 (d, J=3.3 Hz, 1H),6.62 (d, J=3.3 Hz, 1H).

ESI/MS m/e: 341 ([M+H]+, C₁₉H₁₂N₆O)

Retention time (min.): 9

Example 91

2,6-Di-2-furyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (11%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) and 2-furoyl chloride following the procedure described inExample 90.

ESI/MS m/e: 330 ([M+H]+, C₁₈H₁₁N₅O₂)

Retention time (min.): 9

Example 92

2-Cyclopentyl-6-(2-furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (22%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) and cyclopentanecarbonyl chloride following the proceduredescribed in Example 90.

ESI/MS m/e: 332 ([M+H]+, C₁₉H₁₇N₅O)

Retention time (min.): 10

Example 93

6-(2-Furyl)-2,5-dipyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (19%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) and 2-isonicotinyl chloride following the proceduredescribed in Example 90.

δ ¹H-NMR (CD₃OD): 8.81 (d, 2H), 8.60 (d, 2H), 8.21 (d, 2H), 7.57 (d,2H), 7.48 (s, 1H), 6.82 (d, 1H), 6.58 (d, 1H).

ESI/MS m/e: 341 ([M+H]+, C₁₉H₁₂N₆O)

Retention time (min.): 8

Example 94

6-(2-Furyl)-2-pyridin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (10%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) and pyridine-2-carbonyl chloride following the proceduredescribed in Example 90.

ESI/MS m/e: 341 ([M+H]+, C₁₉H₁₂N₆O)

Retention time (min.): 9

Example 95

6-(2-Furyl)-2-pyrazin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (10%) from 5-(2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine(Example 87) and pyrazine-2-carbonyl chloride following the proceduredescribed in Example 90.

δ ¹H-NMR (CD₃OD): 9.61 (s, 1H), 8.72 (d, 2H), 8.69 (brs, 2H), 7.73 (d,2H), 7.46 (s, 1H), 6.91 (d, 1H), 6.59 (d, 1H).

ESI/MS m/e: 342 ([M+H]+, C₁₈H₁₁N₇O)

Retention time (min.): 8

Example 96

5-(5-Methyl-2-furyl)-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (49%) from5-(5-methyl-2-furyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 19) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d₆): 8.46 (d, 2H), 7.01 (d, 2H), 6.39 (s, 2H), 6.32 (s,2H), 6.12 (d, 1H), 6.04 (d, 1H), 2.11 (s, 3H).

ESI/MS m/e: 268 ([M+H]+, C₁₄H₁₃N₅O)

Retention time (min.): 6

Example 97

5-(1-Benzofuran-2-yl)-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained (30%) from5-(5-methyl-2-furyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 20) following the procedure described in Example 72.

ESI/MS m/e: 304 ([M+H]+, C₁₇H₁₃N₅O)

Retention time (min.): 8

Example 98

5-Pyridin-3-yl-6-pyridin-4-ylpyrazine-2,3-diamine

Obtained as a yellow solid (75%) from5-(3-pyridyl)-6-pyridin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 21) following the same procedure described in Example 72.

ESI/MS m/e: 265 ([M+H]+, C₁₄H₁₂N₆)

Retention time (min.): 3

Example 99

5-Pyridin-3-yl-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

Obtained as yellow solid (88%) from5-pyridin-3-yl-6-pyridin-4-ylpyrazine-2,3-diamine (Example 98) followingthe same procedure described in Example 76.

δ ¹H-NMR (DMSO-d₆): 12.03 (bs, 2H), 8.45 (d, 2H), 8.40 (d, 2H), 7.70 (d,1H), 7.30 (m, 1H), 7.20 (d, 2H).

ESI/MS m/e: 291 ([M+H]+, C₁₅H₁₀N₆O)

Retention time (min.): 5

Example 100

2-(4-Fluorophenyl)-6-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained as a yellow solid (23%) from5-pyridin-3-yl-6-pyridin-4-ylpyrazine-2,3-diamine (Example 98) and4-fluorobenzoyl chloride following the same procedure described inExample 90.

ESI/MS m/e: 369 ([M+H]+, C₂₁H₁₃FN₆)

Retention time (min.): 10

Example 101

5-(2-Furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine

Obtained (27%) from5-(2-furyl)-6-pyrimidin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 22) following the procedure described in Example 72.

m.p.: 233.1-234.7° C.

δ ¹H-NMR (DMSO-d₆): 9.00 (s, 1H), 8.75 (d, J=3.0 Hz, 1H), 7.56 (d, J=3.0Hz, 1H), 7.42 (s, 1H), 6.55 (s, 2H), 6.43-6.39 (m, 4H).

ESI/MS m/e: 255 ([M+H]+, C₁₂H₁₀N₆O)

Retention time (min.): 7

Example 102

3-Amino-5-(2-furyl)-6-pyrimidin-4-ylpyrazin-2-ol

Obtained (13%) from 5-(2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine(Example 101) following the procedure described in Example 73.

ESI/MS m/e: 256 ([M+H]+, C₁₂H₉N₁₅O₂)

Retention time (min.): 7

Example 103

6-(2-Furyl)-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (12%) from 5-(2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine(Example 101) following the procedure described in Example 74.

ESI/MS m/e: 265 ([M+H]+, C₁₃H₈N₆O)

Retention time (min.): 8

Example 104

5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one

Obtained from 5-(2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine (Example101) following the procedure described in Example 76. Purification bysilica gel chromatography (CH₂Cl₂/MeOH/NH₃ 50:8:1) provided the titlecompound (23 mg, 21%).

δ ¹H-NMR (DMSO-d₆): 12.05 (brs, 2H), 9.13 (s, 1H), 8.89 (d, 1H), 7.69(d, 1H), 7.52 (s, 1H), 6.65 (s, 1H), 6.53 (s, 1H).

ESI/MS m/e: 281 ([M+H]+, C₁₃H₈N₆O₂)

Retention time (min.): 8

Example 105

6-(2-Furyl)-2-pyridin-3-yl-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine

Obtained (45%) from 5-(2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine(Example 101) and nicotinoyl chloride hydrochloride following theprocedure described in Example 90.

δ ¹H-NMR (DMSO-d₆): 9.44 (d, 1H), 9.19 (s, 1H), 8.98 (d, 1H), 8.70 (dd,1H), 8.61 (m, 1H), 7.86 (d, 1H), 7.66 (dd, 1H), 7.59 (brs, 1H), 6.80 (d,1H), 6.59 (m, 1H).

ESI/MS m/e: 342 ([M+H]+, C₁₈H₁₁N₇O)

Retention time (min.): 13

Example 106

5-(2-Furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine

Obtained (92%) from5-(2-furyl)-6-[2-(methylthio)pyrimidin-4-yl][1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 23) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d₆): 8.55 (d, J=5.1 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J=5.1Hz, 1H), 6.62 (s, 2H), 6.48-6.43 (m, 4H), 2.18 (s, 3H).

ESI/MS m/e: 301 ([M+H]+, C₁₃H₁₂N₆OS)

Retention time (min.): 11

Example 107

3-Amino-5-(2-furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazin-2-ol

Obtained (39%) from5-(2-furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine(Example 106) following the procedure described in Example 73.

ESI/MS m/e: 302 ([M+H]+, C₁₃H₁₁N₅O₂S)

Retention time (min.): 11

Example 108

6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-Imidazo[4,5-b]pyrazine

Obtained (35%) from5-(2-furyl)-6-[2-(methylthio)pyrimidin-4-yl]pyrazine-2,3-diamine(Example 106) following the procedure described in Example 74.

δ ¹H-NMR (DMSO-d₆): 8.96 (s, 1H), 8.79 (d, 1H), 7.66 (s, 1H), 7.59 (d,1H), 6.84 (s, 1H), 6.62 (s, 1H), 2.26 (s, 3H).

ESI/MS m/e: 311 ([M+H]⁺, C₁₄H₁₀N₆OS)

Retention time (min.): 11

Example 109

5-(3-Methyl-2-furyl)-6-pyrimidin-4-ylpyrazine-2,3-diamine

Obtained (27%) from5-(3-methyl-2-furyl)-6-pyrimidin-4-yl[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 24) following the procedure described in Example 72.

m.p.: 198.0-199.5° C.

δ ¹H-NMR (DMSO-d₆): 8.91 (s, 1H), 8.69 (d, 1H), 7.51 (d, 1H), 7.37 (s,1H), 6.56 (s, 2H), 6.41 (s, 2H), 6.29 (s, 1H), 1.79 (s, 3H).

ESI/MS m/e: 269 ([M+H]+, C₁₃H₁₂N₆O)

Retention time (min.): 8

Example 110

5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)pyrazine-2,3-diamine

Obtained (60%) from5-[2-(methylthio)pyrimidin-4-yl]-6-(2-thienyl)[1,2,5]thiadiazolo[3,4-b]pyrazine(Preparation 25) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d₆): 8.58 (d, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 6.89 (dd,1H), 6.64 (d, 1H), 6.58 (s, 2H), 6.41 (s, 2H), 2.20 (s, 3H).

ESI/MS m/e: 317 ([M+H]+, C₁₃H₁₂N₆S₂)

Retention time (min.): 11

Example 111

5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)-1H-imidazo[4,5-b]pyrazine

Obtained (33%) from5-[2-(methylthio)pyrimidin-4-yl]-6-(2-thienyl)pyrazine-2,3-diamine(Example 110) following the procedure described in Example 74.

ESI/MS m/e: 327 ([M+H]+, C₁₄H₁₀N₆S₂)

Retention time (min.): 12

Example 112

3-(2-Furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine

A mixture of potassium t-butoxide (45 mg, 0.40 mmol) inN-methylpyrrolidone (1 mL) was stirred under nitrogen and a solution of3-ethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 65, 50 mg,0.19 mmol) in N-methylpyrrolidone (1 mL) was added. The mixture wasstirred at room temperature overnight, partitioned between water andethyl acetate, the aqueous phase was extracted twice with ethyl acetate,the organic extracts washed with water and brine, dried (MgSO₄) andconcentrated under vacuum. Silica gel flash column chromatography(dichloromethane/methanol 95:5) gave the title compound as a yellowsolid (20 mg, 40%).

δ ¹H-NMR (DMSO-d₆): 12.30 (bs, 1H), 8.60 (d, 1H), 8.05 (d, 1H), 7.65 (s,1H), 7.45 (d, 2H), 6.70 (d, 1H), 6.55 (s, 2H).

ESI/MS m/e: 263 ([M+H]+, C₁₆H₁₀N₄O)

Retention time (min.): 7

Example 113

3-(2-Furyl)-6-phenyl-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine

Obtained as a brown solid (54%) from6-(2-furyl)-3-(phenylethynyl)-5-pyridin-4-ylpyrazin-2-amine (Example 66)following the same procedure described in Example 112.

δ ¹H-NMR (CDCl₃): 9.75 (bs, 1H), 8.70 (d, 2H), 7.50 (m, 5H), 7.35 (s,1H), 7.05 (s, 1H), 6.30 (m, 2H).

ESI/MS m/e: 339 ([M+H]+, C₂₁H₁₄N₄O)

Retention time (min.): 12

Example 114

6-Cyclohexyl-3-(2-furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine Step a3-Cyclohexylethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

Obtained as a brown solid (39%) from3-bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62) andcyclohexylacetylene following the same procedure of Example 65 (Step a).

Step b

The title compound of Example 114 was obtained as a brown solid (18%)from 3-cyclohexylethynyl-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-aminefollowing the same procedure described in Example 112.

ESI/MS m/e: 339 ([M+H]+, C₂₁H₂₀N₄O)

Retention time (min.): 14

Example 115

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

Obtained as a white solid (89%) from6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-amine (Preparation 10, stepa) and pyridin-3-ylboronic acid following the procedure of Example 1.

¹H-NMR (CDCl₃): 8.65 (bs, 2H), 8.50 (d, 1H), 8.35 (s, 1H), 8.10 (s, 1H),7.65 (d, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 4.90 (bs, 2H).

ESI/MS m/e: 267 ([M+H]⁺, C₁₄H₁₀FN₅).

Retention time (min.): 8

Example 116

5-(3,5-Difluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

Obtained as a brownish solid (31%) from5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6,) and3,5-difluoro-4-tributylstannylpyridine following the procedure ofPreparation 9.

δ ¹H-NMR (DMSO-d6): 8.49 (broad s, 4H), 8.04 (s, 1H), 7.68 (dt, 1H),7.34 (dd, 1H), 7.15 (broad s, 2H).

ESI/MS m/e: 286 ([M+H]+, C₁₄H₉F₂N₅)

Example 117

N-[6-(6-Hydroxypyridin-3-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamideStep a

N-[6-(6-Benzyloxypyridin-3-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a grey solid (78%) fromN-(6-chloro-5-pyridin-4-ylpyrazin-2-yl)cyclopropanecarboxamide(Preparation 8) and2-benzyloxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine*following the same procedure of Example 1. *Prepared according toBouillon A. et al. Tetrahedron 2002, 58, 4369-4373.

¹H-NMR (CDCl₃): 9.55 (s, 1H), 8.55 (d, 2H), 8.30 (d, 2H), 7.60 (d, 1H),7.50 (m, 2H), 7.30 (m, 5H), 6.75 (d, 1H), 5.40 (s, 2H), 1.60 (m, 1H),1.20 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 424 ([M+H]⁺, C₂₅H₂₁N₅O₂).

Retention time (min.): 16

Step b

To a stirred solution ofN-[6-(6-benzyloxypyridin-3-yl)-5-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide(0.22 g, 0.51 mmol) in ethanol (11 mL) was added palladium on activatedcarbon (10%) (0.033 g) and the mixture was hydrogenated underatmospheric pressure. After 18 h, the mixture was filtered, washed withethanol and evaporated under vacuum to provide the titled compound as abrown solid (0.046 g, 27%).

¹H-NMR (DMSO-d₆): 11.25 (s, 1H), 9.30 (s, 1H), 8.60 (d, 2H), 7.50 (m,3H), 7.35 (m, 2H), 6.30 (d, 1H), 2.05 (m, 1H), 0.95 (m, 4H).

ESI/MS m/e: 334 ([M+H]⁺, C₁₈H₁₅N₅O₂).

Retention time (min.): 8

Example 118

1-Cyclopropyl-3-(6-(pyridin-2-yl)-5-(pyridin-4-yl)pyrazin-2-yl)urea Stepa Isocyanatocyclopropane

To a solution of cyclopropanecarboxylic acid (0.230 ml, 2.91 mmol) intoluene (2 ml) at 0° C. under nitrogen atmosphere, triethylamine (0.400ml, 2.90 mmol) and diphenylphosphoryl azide (0.625 ml, 2.90 mmol) weresequentially added. The crude mixture was stirred at room temperaturefor 3 hours and at 80° C. for 3.5 hours and it was used in the next stepwithout further elaboration.

Step b

To a suspension of 60% sodium hydride in mineral oil (0.014 g, 0.353mmol) in DMF (0.5 ml) under nitrogen atmosphere, a solution of6-pyridin-2-yl-5-pyridin-4-ylpyrazin-2-amine (Example 12) (0.080 g,0.321 mmol) was added dropwise. After stirring for 20 minutes at roomtemperature, the crude mixture obtained in step a was added. The mixturewas stirred at room temperature for 16 hours and it was partitionedbetween water and ethyl acetate. The organic layer was dried (Na₂SO₄)and evaporated. The residue was purified with flash silica gelchromatography (95:5 dichloromethane/methanol). Concentration in vacuoof the product-rich fractions provided the titled compound (15 mg, 19%).

¹H-NMR (CDCl₃): 8.63-8.62 (m, 2H), 8.55-8.52 (m, 2H), 7.80-7.71 (m, 1H),7.48-7.44 (m, 1H), 7.39-7.33 (m, 1H), 7.28-7.25 (m, 2H), 2.83-2.81 (m,1H), 0.87-0.83 (m, 2H), 0.65-0.62 (m, 2H)

ESI/MS m/e: 333 ([M+H]⁺, C₁₈H₁₆N₆O)

Example 119

N-[5-(3-Fluoropyridin-4-yl)-6-(6-methoxypyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (11%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridinefollowing the same procedure of Example 1.

¹H-NMR (CDCl₃): 9.60 (s, 1H), 8.55 (d, 1H), 8.40 (s, 1H), 8.20 (m, 2H),7.65 (m, 2H), 6.75 (d, 1H), 3.95 (s, 3H), 1.60 (m, 1H), 1.20 (m, 2H),0.95 (m, 2H).

ESI/MS m/e: 366 ([M+H]⁺, C₁₉H₁₆FN₅O₂).

Retention time (min.): 13

Example 120

N-[5,6-bis(3-Fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a light yellow solid (12%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine*following the procedure of Example 1. *Prepared according to Bouillon A.et al. Tetrahedron 2002, 58, 4369-4373.

¹H-NMR (CDCl₃): 9.75 (s, 1H), 8.55 (m, 2H), 8.40 (s, 1H), 8.35 (s, 1H),8.25 (s, 1H), 7.55 (dd, 1H), 7.40 (dd, 1H), 7.30 (s, 1H), 1.60 (m, 1H),1.20 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 354 ([M+H]⁺, C₁₈H₁₃F₂N₅O).

Retention time (min.): 12

Example 121

N-[5-(3-Fluoropyridin-4-yl)-6-quinolin-3-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (22%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and isoquinoline-4-boronic acid following the sameprocedure of Example 1.

¹H-NMR (CDCl₃): 9.70 (s, 1H), 9.00 (s, 1H), 8.55 (d, 1H), 8.45 (s, 1H),8.30 (s, 1H), 8.10 (m, 2H), 7.65 (m, 4H), 1.70 (m, 1H), 1.15 (m, 2H),1.00 (m, 2H).

ESI/MS m/e: 386 ([M+H]⁺, C₂₂H₁₆FN₅O).

Retention time (min.): 13

Example 122

N-[5-(3-Fluoropyridin-4-yl)-6-(5-methoxypyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (50%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridinefollowing the same procedure of Example 1.

¹H-NMR (CDCl₃): 9.60 (s, 1H), 8.50 (m, 2H), 8.35 (m, 2H), 7.60 (m, 1H),7.20 (m, 2H), 3.75 (s, 3H), 1.65 (m, 1H), 1.20 (m, 2H), 0.95 (m, 2H).

ESI/MS m/e: 366 [M+H]⁺, C₁₉H₁₆FN₅O₂).

Retention time (min.): 12

Example 123

N-[5-(3-Fluoropyridin-4-yl)-6-(6-hydroxypyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide Step aN-[6-(6-Benzyloxypyridin-3-yl)-5-(3-fluoropyridin)-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a brown solid (43%) fromN-[6-Chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and2-benzyloxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine*following the same procedure of Example 1. *Prepared according toBouillon A. et al. Tetrahedron 2002, 58, 4369-4373.

ESI/MS m/e: 442 ([M+H]⁺, C₂₅H₂₀FN₅O₂).

Step b

To a stirred solution ofN-[6-(6-benzyloxypyridin-3-yl)-5-(3-fluoropyridin)-4-ylpyrazin-2-yl]cyclopropanecarboxamide(0.13 g, 0.29 mmol) in ethanol (10 mL) was added palladium on activatedcarbon (10%) (0.033 g) and the mixture was hydrogenated underatmospheric pressure. After 18 h, the mixture was filtered, washed withethanol and evaporated under vacuum to provide the titled compound as abrown solid (0.04 g, 40%).

¹H-NMR (DMSO-d₆): 11.65 (bs, 1H), 11.35 (s, 1H), 9.35 (s, 1H), 8.55 (m,2H), 7.65 (m, 1H), 7.40 (m, 2H), 6.30 (dd, 1H), 2.00 (m, 1H), 0.95 (d,4H).

ESI/MS m/e: 352 ([M+H]⁺, C₁₈H₁₄FN₅O₂).

Retention time (min.): 10

Example 124

N-[5-(3-Fluoropyridin-4-yl)-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide

In a sealed tube three cycles of vacuum and argon were applied to amixture of Preparation 27 (0.15 g, 0.45 mmol),3-fluoro-4-stannylpyridine (0.19 g, 0.49 mmol) and CuI (0.01 g, 0.04mmol). DMF (5 mL) was added and argon was bubbled for 5 min, afterwhich, Pd(Ph₃P)₂Cl₂ (0.02 g, 0.02 mmol) was added and argon was againbubbled for 5 min. The reaction mixture was heated at 120° C. for 2 h.Upon the reaction was completed the mixture was diluted with EtOAc (20mL) and H₂O (20 mL) and filtered over celite. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel, eluting with a MeOH/CH₂Cl₂ gradient(0→20%), yielding the desired product that was precipitated with Et₂O (3mL) as a pale yellow solid (0.08 g, 51%).

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.49 (s, 1H); 8.58 (s, 1H); 8.29 (s, 1H);8.25 (d, 1H); 7.69 (dd, 1H); 7.4 (dd, 1H); 7.25 (d, 1H); 2.08 (m, 1H);11.53 (s, 1H); 0.93 (s, 2H); 0.91 (s, 2H).

MS (IE) m/e: 351 (M+, 49), 283 (100).

Example 125

N-[5-(3-fluoropyridin-4-yl)-6-pyrimidin-5-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (32%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and 5-trimethylstannylpyrimidine following theprocedure of Preparation 9.

1H-NMR (DMSO-d6): 11.57 (s, 1H), 9.52 (s, 1H), 9.23 (s, 1H), 8.84 (s,2H), 8.58 (m, 1H), 8.55 (m, 1H), 7.70 (m, 1H), 2.10 (m, 1H), 0.92 (d,4H).

ESI/MS m/e: 337 ([M+H]+, C₁₇H₁₃FN₆O)

Example 126

N-[3-(3-fluoropyridin-4-yl)-2,2′-bipyrazin-6-yl]cyclopropanecarboxamide

Obtained as a white solid (23%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and 2-trimethylstannylpyrazine following the procedureof Preparation 9.

δ 1H-NMR (DMSO-d6): 11.58 (s, 1H), 9.47 (s, 1H), 9.21 (d, 1H), 8.66 (d,1H), 8.43 (m, 3H), 7.62 (dd, 1H), 2.11 (m, 1H), 0.91 (d, 4H).

ESI/MS m/e: 337 ([M+H]+, C₁₇H₁₃FN₆O)

Example 127

N-[5-(3-Fluoro-1-oxidopyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide Step aN-[6-Chloro-5-(3-fluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

To a suspension of the title compound of Preparation 10 (2.54 g, 8.66mmol) in CH₂Cl₂ (40 mL), cooled at 0° C., was added m-CPBA (2.78 g,11.26 mmol) in small portions. Upon addition completion the ice bath wasremoved and the reaction continued at room temperature for 20 h. Theprecipitated product was filtered and washed with CH₂Cl₂ (3×10 mL), sat.NaHCO₃ (3×10 mL), H₂O (3×10 mL) and Et₂O (4×10 mL), giving the productas a white powder (2.23 g, 84% yield).

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.39 (s, 1H); 8.73 (d, 1H); 8.29 (d, 1H);7.9 (bs, 1H); 7.68 (m, 2H); 2.03 (m, 1H); 0.92 (m, 4H)

Step b

In a sealed tube three cycles of vacuum and argon were applied to amixture of theN-[6-chloro-5-(3-fluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(2.23 g, 7.22 mmol), pyridin-3-ylboronic acid (1.15 g, 9.39 mmol) andCs₂CO₃ (7.06 g, 21.66 mmol). A solution of 1,4-dioxane:H₂O (64 mL, 9:1)was added and argon was bubbled for 5 min, after which, PdCl₂dppfCH₂Cl₂(0.59 g, 0.72 mmol) was added and argon was again bubbled other 5 min.The reaction mixture was heated at 90° C. for 1 h. Upon the reactioncompletion the 1,4-dioxane was concentrated in vacuo, and the obtainedresidue was adsorbed onto silica gel with 10% MeOH/THF (150 mL) andpurified by column chromatography on silica gel eluting with aMeOH/EtOAc gradient (0→20%). The green solid obtained was precipitatedwith 1% MeOH/CH₂Cl₂ (5 mL), and washed with 1% MeOH/CH₂Cl₂ (3×3 mL),CH₂Cl₂ (3×5 mL), 1% MeOH/Et₂O (3×5 mL) and Et₂O (4×5 mL) to yield thetitle compound as a white powder (1.41 g, 56%).

¹H-NMR (DMSO-d₆, 300 MHz, δ): 9.44 (s, 1H); 8.69 (s, 1H); 8.62 (d, 1H);8.46 (d, 1H); 8.23 (d, 1H); 7.88 (d, 1H); 7.66 (dd, 1H); 7.45 (dd, 1H);2.1 (m, 1H); 0.92 (s, 2H); 0.9 (s, 2H).

EM (IE) m/e: 351 (M+, 99.9), 283 (100).

Example 128

N-[5-(3-fluoropyridin-4-yl)-6-(5-fluoropyridin-2-yl)pyrazin-2-yl]cyclopropanecarboxamide

An oven dried resealable Schlenk tube was charged with2-bromo-5-fluoropyridine (0.52 g, 2.9 mmol), hexamethylditin (0.97 g,2.9 mmol) and toluene (15 mL). The Schlenk tube was subjected to threecycles of evacuation-backfilling with argon, andtetrakis(triphenylphosphine)palladium (0.162 g, 0.14 mmol) was added.After three new cycles of evacuation-backfilling with argon, the Schlenktube was capped and placed in an oil bath at 80° C. After 5 hours, themixture was cooled andN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10, 0.424 g, 1.45 mmol) and furthertetrakis(triphenylphosphine)palladium (0.162 g, 0.14 mmol) were added.The mixture was heated to 110° C. and stirred overnight. The mixture wasconcentrated, ethyl acetate was added and the organic solution waswashed with 4% aqueous sodium bicarbonate solution, brine, dried (MgSO₄)and evaporated. The residue was purified by silica gel chromatography(CH₂Cl₂/MeOH 98:2). The appropriate fractions were concentrated to leavea solid which, upon washing with a mixture of hexane and ethyl acetate,gave the title compound (0.077 g, 15%) as an off-white solid.

δ 1H-NMR (DMSO-d6): 11.47 (s, 1H), 9.46 (s, 1H), 8.47 (m, 1H), 8.44 (m,1H), 8.32 (m, 1H), 8.06 (m, 1H), 7.92 (m, 1H), 7.59 (m, 1H), 2.08 (m,1H), 0.90 (d, 4H).

ESI/MS m/e: 354 ([M+H]+, C₁₈H₁₃F₂N₅O)

Example 129

N-[6-(2-Fluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropane-carboxamide

Obtained as a white solid (28%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and 2-fluorophenylboronic acid following the procedureof Example 1.

δ ¹H-NMR (DMSO-d6): 8.69 (m, 1H), 8.54 (m, 1H), 7.90 (m, 1H), 7.64 (s,1H), 7.45 (m, 1H), 6.80 (m, 1H), 6.52 (m, 1H), 6.40 (m, 1H), 2.07 (m,1H), 0.99 (d, 4H).

ESI/MS m/e: 353 ([M+H]+, C₁₉H₁₄F₂N₄O)

Example 130

N-[6-(2,4-Difluorophenyl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropane-carboxamide

Obtained as a white solid (19%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and 2,4-difluorophenylboronic acid following theprocedure of Example 1.

δ ¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.47 (m, 1H), 8.36 (m, 1H), 8.25 (s,1H), 7.44 (m, 2H), 6.94 (m, 1H), 6.74 (m, 1H), 1.60 (m, 1H), 1.20 (m,2H), 1.00 (d, 2H).

ESI/MS m/e: 371 ([M+H]+, C₁₉H₁₃F₃N₄O)

Example 131

N-[5-(3-Fluoropyridin-4-yl)-6-(1,3-oxazol-2-yl)pyrazin-2-yl]cyclopropane-carboxamide

Obtained as a white solid (65%) fromN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10) and (1,3-oxazol-2-yl)zinc chloride following theprocedure of Example 20, step b.

δ ¹H-NMR (DMSO-d6): 11.66 (s, 1H), 9.52 (s, 1H), 8.56 (m, 2H), 8.30 (s,1H), 7.65 (m, 1H), 7.34 (s, 1H), 2.10 (m, 1H), 0.90 (d, 4H).

ESI/MS m/e: 326 ([M+H]+, C₁₆H₁₂FN₅O₂)

Example 132

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]propanamide

To a solution of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Example 115) (150 mg, 0.56 mmol) in CH₂Cl₂ (5 mL) was added pyridine (1mL), cooled at 0° C., propionyl chloride (57 mg, 0.62 mmol) was addeddropwise. Upon complete addition, the ice bath was removed and thereaction continued at room temperature overnight. Then CH₂Cl₂ (10 mL)and aqueous NaOH 10% (10 mL) were added, the organic layer wasseparated, and washed with H₂O and saturated NaCl. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography on silica gel,eluting with an EtOAc/hexane gradient (80→100%), yielding the targetproduct (100 mg, 55%)

¹H-NMR (CDCl₃, 250 MHz, δ): 9.71 (s, 1H); 9.17 (s, 1H); 8.83 (d, 1H);8.6 (dd, 1H); 8.54 (d, 1H); 8.34 (d, 1H); 7.61 (m, 2H); 7.22 (dd, 1H);2.57 (q, 2H); 1.31 (t, 3H)

Example 133

2-Cyclopentyl-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide

The title compound was obtained as a white solid (41%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andcyclopentylacetyl chloride following the same procedure of Example 132.

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.5 (s, 1H); 8.61-8.51 (m, 3H); 8.5 (d,1H); 7.79 (dt, 1H); 7.68 (dd, 1H); 7.4 (ddd, 1H); 2.27 (m, 1H); 11.15(s, 1H); 1.77 (m, 2H); 1.57 (m, 6H); 1.2 (m, 2H).

Example 134

N-[3-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopentanecarboxamide

The title compound was obtained as a white solid (58%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andcyclopentanecarbonyl chloride following the same procedure of Example132.

¹H-NMR (CDCl₃, 250 MHz, δ): 9.69 (s, 1H); 8.71 (bs, 1H); 8.61 (d, 1H);8.54 (d, 1H); 8.43 (s, 1H); 8.33 (d, 1H); 7.65 (dt, 1H); 7.59 (d, 1H);7.25 (dd, 1H); 2.87 (m, 1H); 2.08-1.56 (m, 8H)

Example 135

3,3,3-Trifluoro-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]propanamide

The title compound was obtained as a white solid (13%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) and3,3,3-trifluoropropionyl chloride following the same procedure ofExample 132.

¹H-NMR (CDCl₃, 250 MHz, δ): 9.89 (bs, 1H); 9.7 (s, 1H); 8.92 (s, 1H);8.61 (dd, 1H); 8.57 (dd, 1H); 8.36 (s, 1H); 7.65-7.55 (m, 2H); 7.24 (m,1H); 3.43 (q, 2H)

Example 136

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclobutanecarboxamide

The title compound was obtained as a yellowish solid (91%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andcyclobutanecarbonyl chloride following the same procedure of Example132.

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.58 (s, 1H); 8.88 (s, 1H); 8.85 (s, 1H);8.59 (m, 2H); 8.28 (d, 1H); 7.85 (dd, 1H); 7.73 (dd, 1H); 3.46 (m, 1H);2.36-2.05 (m, 4H); 2.05-1.75 (m, 2H)

Example 137

N-[3-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide

The title compound was obtained as a white solid (41%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andacetyl chloride following the same procedure of Example 132.

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.5 (s, 1H); 8.73 (s, 2H); 8.55 (m, 2H);8.04 (d, 1H); 7.73-7.61 (m, 2H); 2.2 (s, 3H)

Example 138

2-Cyclopropyl-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide

The title compound was obtained as a white solid (20%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andcyclopropylacetyl chloride following the same procedure of Example 132.

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.51 (s, 1H); 8.54 (m, 4H); 7.79 (dt, 1H);7.67 (dd, 1H); 7.4 (dd, 1H); 2.38 (d, 2H); 11.11 (s, 1H); 1.16 (m, 1H);0.53-0.46 (m, 2H); 0.24-0.18 (m, 2H)

Example 139

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2-morpholin-4-ylacetamideStep a2-Chloro-N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]acetamide

The title compound was obtained as a white solid (91%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andchloroacetyl chloride following the same procedure of Example 132.

Step b

To a solution of the previously obtained chloroacetamide (0.235 g, 0.68mmol) and morpholine (0.07 mL, 0.75 mmol) in DMF (7 mL) was added K₂CO₃(0.19 g, 1.36 mmol) and the reaction mixture was heated at 60° C. for 1h. Upon reaction completion, the solvent was concentrated in vacuo. Theresidue was diluted with CH₂Cl₂ (5 mL) and washed with sat. NaCl (1×5mL) and H₂O (1×5 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by columnchromatography on silica gel, eluting with an EtOAc/hexane gradient(80→100%), yielding the desired product as a white powder (0.179 g, 67%yield).

¹H-NMR (DMSO-d₆, 250 MHz, δ): 9.5 (s, 1H); 8.59 (m, 3H); 8.53 (d, 1H);7.82 (dt, 1H); 7.7 (t, 1H); 7.43 (dd, 1H); 3.64 (m, 6H); 2.58 (m, 4H)

Example 140

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]-2-methylpropanamide

The title compound was obtained as a white solid (53%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andisobutyryl chloride following the same procedure of Example 132.

¹H-NMR (CDCl₃, 250 MHz, δ): 9.71 (s, 1H); 8.96 (s, 1H); 8.8 (d, 1H);8.61 (dd, 1H); 8.53 (d, 1H); 8.33 (s, 1H); 7.6 (m, 2H); 7.23 (dd, 1H);2.72 (m, 1H); 1.33 (s, 3H); 1.31 (s, 3H)

Example 141

N-[5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]methanesulfonamide

The title compound was obtained as an off-white solid (49%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) andmethanesulfonyl chloride following the same procedure of Example 132.

¹H-NMR (DMSO-d₆, 250 MHz, δ): 8.6-8.45 (m, 3H); 8.41 (s, 1H); 8.34 (s,1H); 7.79 (d, 1H); 7.66 (dd, 1H); 7.4 (m, 1H); 3.33 (s, 3H)

Example 142

N-[5-(3,5-Difluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (40%) fromN-[6-chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 26) and pyridin-3-ylboronic acid following the sameprocedure of Example 1.

¹H-NMR (CDCl₃): 9.65 (s, 1H), 8.70 (m, 2H), 8.50 (s, 1H), 8.35 (s, 2H),7.65 (d, 1H), 7.25 (m, 1H), 1.60 (m, 1H), 1.25 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 354 ([M+H]⁺, C₁₈H₁₃F₂N₅O).

Retention time (min.): 11

Example 143

N-[5-(3,5-Difluoropyridin-4-yl)-6-pyridin-4-ylpyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (39%) fromN-[6-chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 26) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following thesame procedure of Example 1.

¹H-NMR (CDCl₃): 9.75 (s, 1H), 8.65 (bs, 2H), 8.35 (s, 2H), 8.25 (s, 1H),7.25 (m, 2H), 1.65 (m, 1H), 1.25 (m, 2H), 1.00 (m, 2H).

ESI/MS m/e: 354 ([M+H]⁺, C₁₈H₁₃F₂N₅O).

Retention time (min.): 11

Example 144

N-[5-(3,5-difluoropyridin-4-yl)-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide

Obtained as a white solid (19%) fromN-[5-bromo-6-(1-oxidopyridin-3-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 27) and 3,5-difluoro-4-(tributylstannyl)pyridine followingthe procedure of Example 124.

δ 1H-NMR (DMSO-d6): 11.59 (s, 1H), 9.50 (s, 1H), 8.63 (s, 2H), 8.31 (s,1H), 8.24 (m, 1H), 7.37 (m, 1H), 7.22 (m, 1H), 2.07 (m, 1H), 0.90 (d,4H).

ESI/MS m/e: 370 ([M+H]+, C₁₈H₁₃F₂N₅O₂)

Example 145

N-[5-(3,5-difluoro-1-oxidopyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropane-carboxamideStep aN-[6-chloro-5-(3,5-difluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropane-carboxamide

The title compound was obtained as a white solid (72%) fromN-[6-chloro-5-(3,5-difluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 26) following the same procedure of Example 127, step a.

δ 1H-NMR (DMSO-d6): 11.71 (s, 1H), 9.41 (s, 1H), 8.74 (m, 2H), 2.10 (m,1H), 0.90 (d, 4H).

ESI/MS m/e: 327 ([M+H]+, C₁₃H₉ClF₂N₄O₂)

Step b

The title compound was obtained as a white solid (12%) fromN-[6-chloro-5-(3,5-difluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamideand pyridin-3-ylboronic acid following the procedure of Example 127,step b.

δ 1H-NMR (DMSO-d6): 11.57 (s, 1H), 9.43 (s, 1H), 8.71 (s, 1H), 8.60 (m,3H), 7.87 (m, 1H), 7.42 (m, 1H), 2.03 (m, 1H), 0.90 (d, 4H).

ESI/MS m/e: 370 ([M+H]+, C₁₈H₁₃F₂N₅O₂)

Example 146

N-[6-(3,5-Difluoropyridin-2-yl)-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide

In a Schlenk tube were chargedN-[6-chloro-5-(3-fluoropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide(Preparation 10, 70 mg, 0.24 mmol),3,5-difluoro-2-tributylstannanyl-4-trimethylsilylpyridine (preparedaccording to the procedure described in J. Med. Chem. 2006, 49 (1),35-38) (177.6 mg, 0.48 mmol), copper(I) iodide (2.28 mg, 12 μmol),lithium chloride (previously dried) (10.14 mg, 0.24 mmol) and dioxane(1.5 mL). The mixture was submitted to three vacuum-argon cycles, thentetrakis(triphenylphosphine)palladium(0) (27.64 mg, 24 μmol) was addedand the mixture purged in the same way and the mixture was heated at100° C. for 18 h. The reaction was concentrated, ethyl acetate (1 ml)and HCl 2N (5 ml) were added and the reaction was stirred at roomtemperature for 1 h. Ethyl acetate was added, the organic layer wasseparated, and the aqueous phase was extracted with ethyl acetate. Thecombined extracts were washed with water and the organic layer was driedover magnesium sulphate and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica flash, usingdichloromethane/methanol (100:1) to yield the title compound (23 mg,26%) as a yellowish solid.

δ ¹H-NMR (DMSO-d6): 11.55 (s, 1H), 9.56 (s, 1H), 8.47 (m, 3H), 8.13 (m,1H), 7.57 (m, 1H), 2.08 (m, 1H), 0.92 (d, 4H).

ESI/MS m/e: 372 ([M+H]+.

Example 147

6-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazineStep a3-[(4-Fluorophenyl)ethynyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

Obtained as a brown solid (100%) from3-bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Preparation 28) and 1-ethynyl-4-fluorobenzene following the sameprocedure described in Example 65 (Step a).

ESI/MS m/e: 386 ([M+H]⁺, C₂₂H₁₃F₂N₅).

Step b

The title compound was obtained as a brown solid (46%) from3-[(4-fluorophenyl)ethynyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-aminefollowing the same procedure described in Example 112.

¹H-NMR (DMSO-d₆): 12.95 (bs, 1H), 8.50 (m, 4H), 8.10 (dd, 2H), 7.70 (m,2H), 7.35 (m, 3H), 7.25 (s, 1H).

ESI/MS m/e: 386([M+H]⁺, C₂₂H₁₃F₂N₅).

Retention time (min.): 13

Example 148

2-(3-Fluoropyridin-4-yl)-6-pyridin-2-yl-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazineStep a5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-3-(pyridin-2-ylethynyl)pyrazin-2-amine

Obtained as a brown solid (100%) from3-bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Preparation 28) and 2-ethynylpyridine following the same proceduredescribed in Example 65 (Step a).

¹H-NMR (CDCl₃): 8.70 (m, 3H), 8.55 (d, 1H), 8.35 (s, 1H), 7.80 (m, 4H),7.605 (dd, 1H), 7.35 (m, 1H), 5.70 (s, 2H).

ESI/MS m/e: 369 [M+H]⁺, C₂₁H₁₃FN₆).

Step b

The title compound was obtained as a brown solid (38%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-3-(pyridin-2-ylethynyl)pyrazin-2-aminefollowing the same procedure described in Example 112.

ESI/MS m/e: 369 [M+H]⁺, C₂₁H₁₃FN₆).

Retention time (min.): 11

Example 149

2-(3-Fluoropyridin-4-yl)-3,6-dipyridin-3-yl-5H-pyrrolo[2,3-b]pyrazineStep a5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-3-(pyridin-3-ylethynyl)pyrazin-2-amine

Obtained as a yellow solid (100%) from3-bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Preparation 28) and 3-ethynylpyridine following the same proceduredescribed in Example 65 (Step a).

ESI/MS m/e: 369 [M+H]⁺, C₂₁H₁₃FN₆).

Step b

The title compound was obtained as a brown solid (36%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-3-(pyridin-3-ylethynyl)pyrazin-2-aminefollowing the same procedure described in Example 112.

¹H-NMR (DMSO-d₆): 13.10 (bs, 1H), 9.25 (s, 1H), 8.60 (d, 1H), 8.50 (m,5H), 7.70 (m, 2H), 7.55 (dd, 1H), 7.40 (s, 1H), 7.35 (m, 1H).

ESI/MS m/e: 369 ([M+H]⁺, C₂₁H₁₃FN₆).

Retention time (min.): 10

Example 150

4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitrileStep a4-{[3-Amino-6-(3-fluoropyridin-4-yl)-5-pyridin-3-ylpyrazin-2-yl]ethynyl}benzonitrile

Obtained as a brown solid (100%) from3-bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Preparation 28) and 4-ethynylbenzonitrile following the same proceduredescribed in Example 65 (Step a).

ESI/MS m/e: 393 [M+H]⁺, C₂₃H₁₃FN₆).

Step b

The title compound was obtained as a brown solid (53%) from4-[{3-amino-6-(3-fluoropyridin-4-yl)-5-pyridin-3-ylpyrazin-2-yl]ethynyl}benzonitrilefollowing the same procedure described in Example 112.

ESI/MS m/e: 393 ([M+H]⁺, C₂₁H₁₃FN₆).

Retention time (min.): 13

Example 151

4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzamide

To a stirred solution of4-[2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitrile(Example 150) (0.050 g, 0.12 mmol) in ethanol (1.5 mL) was added a 2Naqueous solution of sodium hydroxide (0.127 mL, 0.25 mmol) and themixture was stirred at 80° C. After 18 h, ethanol was evaporated and theaqueous phase was acidified until pH=6 with a 2N aqueous solution ofhydrochloric acid. The resulting solid was filtered, washed with waterand dried to furnish the titled compound (0.018 g, 36%) as a brownsolid.

ESI/MS m/e: 411 ([M+H]⁺, C₂₃H₁₅FN₆O).

Retention time (min.): 10

Example 152

2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine Step a3-Ethynyl-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine

Obtained as a yellow solid (72%) from3-bromo-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine(Preparation 28) and trimethylsilylacetylene following the sameprocedure described in Example 65 (steps a and b).

δ 1H-NMR (CDCl₃): 8.73-8.45 (m, 3H), 7.86-7.32 (m, 4H), 5.73 (s, 2H),5.74 (s, 1H).

ESI/MS m/e: 292 ([M+H]+, C₁₆H₁₀FN₅)

Step b

The title compound was obtained as a yellow solid (28%) from3-ethynyl-5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-aminefollowing the same procedure described in Example 112.

δ ¹H-NMR (DMSO-d6): 8.53-8.50 (m, 2H), 8.47 (m, 1H), 8.10 (d, 1H),7.79-7.65 (m, 3H), 7.37 (m, 1H), 6.77 (d, 1H).

ESI/MS m/e: 292 ([M+H]+, C₁₆H₁₀FN₅)

Example 153

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine

Obtained as a white solid (70%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl[1,2,5]thiadiazolo-[3,4-b]pyrazine(Preparation 29) following the procedure described in Example 72.

δ ¹H-NMR (DMSO-d6): 7.52 (m, 4H), 6.72 (m, 1H), 6.6 (dd, 1H), 6.39 (ddd,1H), 5.68 (s, 2H), 5.55 (s, 2H).

ESI/MS m/e: 283 ([M+H]+, C₁₄H₁₁FN₆)

Example 154

2-(4-Fluorophenyl)-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine

A mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine(Example 153, 0.100 g, 0.35 mmol) and 4-fluorobenzoyl chloride (0.074 g,0.46 mmol) in pyridine (1 mL) was stirred and heated to 120° C. in asealed tube for 24 hours. Water was added and the filtered solid waspurified by silica gel chromatography eluting with CH₂Cl₂/MeOH (98:1 to95:5) to give the title compound (0.045 g, 33%) as an off-white solid.

δ ¹H-NMR (DMSO-d6): 8.54 (m, 3H), 8.5 (s, 1H), 8.39 (m, 2H), 7.79 (m,1H), 7.69 (dd, 1H), 7.50 (m, 2H), 7.38 (ddd, 1H).

ESI/MS m/e: 387 ([M+H]+, C₂₁H₁₂F₂N₆)

Example 155

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-2-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazine

Obtained as a solid (47%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example158) and 4-(trifluoromethoxy)benzoyl chloride following the proceduredescribed in Example 154.

δ ¹H-NMR (DMSO-d6): 8.54 (m, 3H), 8.50 (s, 1H), 8.45 (m, 2H), 7.79 (dd,1H), 7.69 (dd, 1H), 7.65 (m, 2H), 7.38 (ddd, 1H).

ESI/MS m/e: 453 ([M+H]+, C₂₂H₁₂F₄N₆O)

Example 156

2-[1-(4-Chlorophenyl)ethyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine

Obtained as a solid (28%) from5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example153) and 2-(4-chlorophenyl)propanoyl chloride following the proceduredescribed in Example 154.

δ ¹H-NMR (DMSO-d6): 8.52 (m, 3H), 8.48 (s, 1H), 7.76 (m, 1H), 7.63 (dd,1H), 7.40 (m, 4H), 7.38 (ddd, 1H), 4.55 (q, 1H), 1.74 (d, 3H).

ESI/MS m/e: 431 ([M+H]+, C₂₃H₁₆ClFN₆)

Example 157

5-(3-Fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazineStep a

5-(3-Fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine

A stirred mixture of5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example153, 1.00 g, 3.54 mmol), thiocarbonyldiimidazole (1.28 g, 7.1 mmol) andtriethylamine (0.72 g, 7.1 mmol) in tetrahydrofuran (12 mL) was heatedto 80° C. in sealed tube. After 24 hours, the mixture was cooled andevaporated in vacuo. The residue was purified by silica gelchromatography eluting with dichloromethane/methanol (95:5) to give thetitle compound (0.60 g, 53%) as a beige solid.

δ ¹H-NMR (DMSO-d6): 13.77 (s, 2H), 8.49 (m, 3H), 8.44 (dd, 1H), 7.71 (m,1H), 7.59 (dd, 1H), 7.35 (ddd, 1H).

ESI/MS m/e: 325 ([M+H]+, C₁₅H₉FN₆S)

Step b

To a suspension of sodium hydride (60% in mineral oil, 0.062 g, 1.54mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added dropwise asolution of5-(3-fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine(0.250 g, 0.77 mmol) in N,N-dimethylformamide (5 mL). After 30 minutes,methyl iodide (0.048 μL, 0.77 mmol) was added dropwise and stirring wascontinued at 0° C. After 3 hours, the solvent was evaporated and themixture was partitioned between saturated aqueous ammonium chloridesolution and ethyl acetate. The organic layer was dried (MgSO₄) andevaporated to give the title compound (235 mg, 90%) as an off-whitesolid.

δ ¹H-NMR (DMSO-d6): 8.49 (m, 4H), 7.73 (m, 1H), 7.64 (dd, 1H), 7.36(ddd, 1H), 7.04 (s, 1H), 2.75 (s, 3H).

ESI/MS m/e: 339 ([M+H]+, C₁₆H₁₁FN₆S)

Example 158

5-(3-Fluoropyridin-4-yl)-2-morpholin-4-yl-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazineStep a

5-(3-Fluoropyridin-4-yl)-2-(methylsulfonyl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine

To a cooled (0° C.) solution of5-(3-fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine(Example 157, 0.235 g, 0.69 mmol) in dichloromethane (12 mL) andmethanol (1 mL) was added m-chloroperbenzoic acid (77%, 310 mg, 1.39mmol) in portions. The mixture was then warmed to room temperature andstirred for 3 days. The solid precipitate was filtered and dried to givethe pure title compound (0.06 g, 23%) as a white solid.

HPLC-ESI/MS m/e: 4.58 min ((95% pure), 371 ([M+H]+, C₁₆H₁₁FN₆O₂S))

Step b

A mixture of5-(3-fluoropyridin-4-yl)-2-(methylsulfonyl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazine(0.060 g, 0.16 mmol) and morpholine (1.5 mL) were heated to 120° C. in asealed tube. After 3 hours, the mixture was evaporated and the residuewas purified by silica gel chromatography eluting withdichloromethane/methanol (95:5) to give the title compound (0.029 g,48%) as a white solid.

δ ¹H-NMR (DMSO-d6): 8.47 (m, 4H), 7.67 (m, 1H), 7.58 (dd, 1H), 7.32(ddd, 1H), 3.7 (m, 4H), 3.44 (m, 4H).

ESI/MS m/e: 378 ([M+H]+, C₁₉H₁₆FN₇O)

Example 159

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-N-(2,2,2-trifluoro-1-methylethyl)pyrazin-2-amine

An oven dried resealable Schlenk tube was charged with5-chloro-2-(3-fluoropyridin-4-yl)-3-pyridin-3-ylpyrazine (Preparation30, 0.100 g, 0.35 mmol), 1,1,1-trifluoropropan-2-amine hydrochloride(0.063 g, 0.42 mmol), caesium carbonate (0.273 g, 0.84 mmol), BINAP(0.0065 g, 0.01 mmol) and toluene (2 mL). The Schlehk tube was subjectedto several cycles of evacuation-backfilling with argon, andpalladium(II) acetate (0.0015 g, 0.007 mmol) was added. After three newcycles of evacuation-backfilling with argon, the Schlenk tube was cappedand placed in an oil bath at 100° C. After stirring overnight, themixture was cooled and partitioned between ethyl acetate and water. Theorganic layer was dried (MgSO₄) and evaporated and the residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH 95:5) to give thetitle compound (0.021 g, 17%) as an off-white solid.

δ ¹H-NMR (DMSO-d6): 8.46 (m, 3H), 8.18 (s, 1H), 8.11 (m, 1H), 7.72 (m,1H), 7.57 (dd, 1H), 7.34 (ddd, 1H), 5.13 (dd, 1H), 1.36 (d, 3H).

ESI/MS m/e: 364 ([M+H]+, C₁₇H₁₃F₄N₅)

Example 160

5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-N-(2,2,2-trifluoroethyl)pyrazin-2-amine

Obtained (10%) from the title compound of Preparation 30 and2,2,2-trifluoroethanamine following the procedure described in Example159.

δ ¹H-NMR (CD₃OD): 8.51 (m, 2H), 8.42 (dd, 1H), 8.3 (d, 1H), 8.17 (s,1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.40 (ddd, 1H), 4.27 (q, 2H)

ESI/MS m/e: 350 ([M+H]+, C₁₆H₁₁F₄N₅)

Composition Example 1

50,000 capsules, each containing 100 mgN-[3-(3-fluoropyridin-4-yl)-2,2′-bipyrazin-6-yl]cyclopropanecarboxamide(active ingredient), were prepared according to the followingformulation:

Active ingredient   5 Kg Lactose monohydrate  10 Kg Colloidal silicondioxide 0.1 Kg Corn starch   1 Kg Magnesium stearate 0.2 Kg

Procedure

The above ingredients were sieved through a 60 mesh sieve, and wereloaded into a suitable mixer and filled into 50,000 gelatine capsules.

Composition Example 2

50,000 tablets, each containing 50 mg ofN-[3-(3-fluoropyridin-4-yl)-2,2′-bipyrazin-6-yl]cyclopropanecarboxamide(active ingredient), were prepared from the following formulation:

Active ingredient 2.5 Kg Microcrystalline cellulose 1.95 Kg  Spray driedlactose 9.95 Kg  Carboxymethyl starch 0.4 Kg Sodium stearyl fumarate 0.1Kg Colloidal silicon dioxide 0.1 Kg

Procedure

All the powders were passed through a screen with an aperture of 0.6 mm,then mixed in a suitable mixer for 20 minutes and compressed into 300 mgtablets using 9 mm disc and flat bevelled punches. The disintegrationtime of the tablets was about 3 minutes.

1. A compound of formula (I)

wherein: A is a monocyclic, polycyclic aryl or heteroaryl groupoptionally substituted by one or more substituents each independentlychosen from halogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, C₁₋₄alkoxy, aryl-C₁₋₄alkoxy, C₁₋₄alkylthio,mono or di-C₁₋₄alkylamino, trifluoromethyl, hydroxy and cyano groups; Bis a monocyclic nitrogen-containing heteroaryl group optionallysubstituted by one or more substituents each independently chosen fromhalogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl,aryl, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl andcyano groups; and R², R¹ and the —NH— group to which R¹ is attached,form a moiety chosen from the moiety of formulae (IIa) and (IIb):

wherein: each instance of R^(a) is independently chosen from a hydrogenatom, halogen atoms, —OH, —NH₂, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl,heteroaryl-C₁₋₄alkyl, saturated heterocyclic rings, C₁₋₄alkoxy, andC₁₋₄alkylthio groups; wherein the aryl or heteroaryl groups are eachindependently unsubstituted or substituted with at least one groupchosen from halogen atoms, C₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxy, mono ordi-C₁₋₄alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyland carboxy groups; and R^(b) is chosen from a hydrogen atom, halogenatoms, C₁₋₄alkyl, C₁₋₄alkylamino, aryl-C₁₋₄alkylamino and —NH₂ groups;or a pharmaceutically acceptable salt thereof, or a N-oxide thereof. 2.The compound according to claim 1, wherein A is an optionallysubstituted monocyclic five or six-membered heteroaryl ring or anoptionally substituted phenyl ring.
 3. The compound according to claim1, wherein A is an optionally substituted pyridine, oxazole, furan,pyrazole, pyrazine or phenyl group.
 4. The compound according to claim1, wherein A is an optionally substituted pyridine, oxazol, furan orpyrazol group.
 5. The compound according to claim 4 wherein A is apyridine ring unsubstituted or substituted with alkoxy groups or halogenatoms.
 6. The compound according to claim 1, wherein A is a pyridinering either unsubstituted or substituted with one or two halogen atoms.7. The compound according to claim 6, wherein A is a pyridine ringeither unsubstituted or substituted with one halogen atom.
 8. Thecompound according to claim 1, wherein B is an optionally substitutedmonocyclic, five or six-membered heteroaryl ring having one or twonitrogen atoms.
 9. The compound according to claim 8, wherein B is anoptionally substituted pyridine or pyrimidine group.
 10. The compoundaccording to claim 1, wherein B is a pyridine ring either unsubstitutedor substituted with one or two halogen atoms.
 11. The compound accordingto claim 10 wherein B is a pyridine ring either unsubstituted orsubstituted with one halogen atom. 12-17. (canceled)
 18. The compoundaccording to claim 1, wherein R², R¹ and the —NH— group to which R¹ isattached form a moiety of formula (IIa) or (IIb):

wherein: each instance of R^(a) is chosen from C₃₋₈cycloalkyl groups,saturated heterocyclic rings, and aryl and heteroaryl groups; whereinthe aryl and heteroaryl groups are each independently unsubstituted orsubstituted with one or more halogen atom; and R^(b) is a hydrogen atom.19. The compound according to claim 18, wherein R², R¹ and the —NH—group to which R¹ is attached form a moiety of formula (IIb):

wherein: R^(a) is chosen from C₃₋₈cycloalkyl, saturated heterocyclicrings, aryl and heteroaryl groups; wherein the aryl and heteroarylgroups are each independently unsubstituted or substituted with one ormore halogen atoms.
 20. The compound according to claim 1 chosen from:6-(3-Fluorophenyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(3-Fluorophenyl)-2-methyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;5-(3-Fluorophenyl)-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;6-(3-Fluorophenyl)-5-pyridin-4-yl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazine;6-(2-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;6-(3-Chlorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;6-(3-Fluorophenyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;2-Cyclopentyl-6-(2-furyl)-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;2,6-Di-2-furyl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-2-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-2,5-dipyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-2-pyridin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-2-pyrazin-2-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;5-Pyridn-3-yl-6-pyridin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;2-(4-Fluorophenyl)-6-pyridin-3-yl-5-pyridin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine;5-(2-Furyl)-6-pyrimidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one;6-(2-Furyl)-2-pyridin-3-yl-5-pyrimidin-4-yl-1H-imidazo[4,5-b]pyrazine;6-(2-Furyl)-5-[2-(methylthio)pyrimidin-4-yl]-1H-imidazo[4,5-b]pyrazine;5-[2-(Methylthio)pyrimidin-4-yl]-6-(2-thienyl)-1H-imidazo[4,5-b]pyrazine;3-(2-Furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;3-(2-Furyl)-6-phenyl-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;6-Cyclohexyl-3-(2-furyl)-2-pyridin-4-yl-5H-pyrrolo[2,3-b]pyrazine;6-(4-Fluorophenyl)-2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;2-(3-Fluoropyridin-4-yl)-6-pyridin-2-yl-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;2-(3-Fluoropyridin-4-yl)-3,6-dipyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine;4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitril;4-[2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzamid;2-(3-Fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin;2-(4-Fluorophenyl)-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin;5-(3-Fluoropyridin-4-yl)-6-pyridin-3-yl-2-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazin;2-[1-(4-Chlorophenyl)ethyl]-5-(3-fluoropyridin-4-yl)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin;5(3-Fluoropyridin-4-yl)-2-(methylthio)-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin;and5-(3-Fluoropyridin-4-yl)-2-morpholin-4-yl-6-pyridin-3-yl-1H-imidazo[4,5-b]pyrazin.21. (canceled)
 22. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable diluent orcarrier. 23-24. (canceled)
 25. A method for treating a subject afflictedwith a pathological condition or disease susceptible to amelioration byantagonism of the A_(2B) adenosine receptor, which comprisesadministering to said subject an effective amount of a compound offormula (I)

wherein: A is a monocyclic, polycyclic aryl or heteroaryl groupoptionally substituted by one or more substituents each independentlychosen from halogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, C₁₋₄alkoxy, aryl-C₁₋₄alkoxy, C₁₋₄alkylthio,mono or di-C₁₋₄alkylamino, trifluoromethyl, hydroxy and cyano groups; Bis a monocyclic nitrogen-containing heteroaryl group optionallysubstituted by one or more substituents each independently chosen fromhalogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl,aryl, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl andcyano groups; and either a) R¹ is a group of formula:-L-(CR′R″)_(n)-G wherein L is a direct bond or a linking group chosenfrom —(CO)—, —(CO)O—, —(CO)NR′—, —SO₂— and —SO₂NR′—; R′ and R″ are eachindependently chosen from a hydrogen atom and C₁₋₄alkyl groups; n is aninteger from 0 to 6; and G is chosen from a hydrogen atom and C₁₋₄alkyl,aryl, heteroaryl, C₃₋₈cycloalkyl and saturated or unsaturatedheterocyclic groups, wherein the C₁₋₄alkyl, C₃₋₈cycloalkyl, aryl orheteroaryl groups are each independently unsubstituted or substitutedwith one or more substituents chosen from halogen atoms, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl,trifluoromethoxy, carbamoyl, carboxy and cyano groups; and R² is chosenfrom a hydrogen atom, halogen atoms and C₁₋₄alkyl, C₂₋₅alkenyl,C₂₋₅alkynyl, C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino,C₁₋₄alkoxy-(CO)—, —NH₂, mono or di-C₁₋₄alkylamino-(CO)— and cyanogroups, wherein the C₁₋₄alkyl, C₂₋₅alkenyl and C₂₋₅alkynyl groups may beeach independently unsubstituted or substituted by one aryl orheteroaryl group; or b) R², R¹ and the —NH— group to which R¹ isattached, form a moiety chosen from the moiety of formulae (IIa) and(IIb):

wherein: each instance of R^(a) is independently chosen from a hydrogenatom, halogen atoms, —OH, —NH₂, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl,heteroaryl-C₁₋₄alkyl, saturated heterocyclic rings, C₁₋₄alkoxy, andC₁₋₄alkylthio groups; wherein the aryl or heteroaryl groups are eachindependently unsubstituted or substituted with at least one groupchosen from halogen atoms, C₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxy, mono ordi-C₁₋₄alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyland carboxy groups; and R^(b) is chosen from a hydrogen atom, halogenatoms C₁₋₄alkyl, C₁₋₄alkylamino, aryl-C₁₋₄alkylamino and —NH, groups; ora pharmaceutically acceptable salt thereof, or a N-oxide thereof; withthe proviso that the compound is not chosen fromN-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide,N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamideandN-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide.26. The method according to claim 25, wherein the pathological conditionor disease is chosen from asthma, bronchoconstriction, allergicdiseases, hypertension, atherosclerosis, reperfusion injury, myocardialischemia, retinopathy, inflammation, gastrointestinal tract disorders,cell proliferation disorders, diabetes mellitus, and autoimmunediseases.
 27. A composition comprising: (i) a compound of formula (I)

wherein: A is a monocyclic, polycyclic aryl or heteroaryl groupoptionally substituted by one or more substituents each independentlychosen from halogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, C₁₋₄alkoxy, aryl-C₁₋₄alkoxy, C₁₋₄alkylthio,mono or di-C₁₋₄alkylamino, trifluoromethyl, hydroxy and cyano groups; Bis a monocyclic nitrogen-containing heteroaryl group optionallysubstituted by one or more substituents each independently chosen fromhalogen atoms, C₁₋₄alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl,aryl, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl andcyano groups; and either a) R¹ is a group of formula;-L-(CR′R″)_(n)-G wherein L is a direct bond or a linking group chosenfrom —(CO)—, —(CO)O—, —(CO)NR′—, —SO₂— and —SO₂NR′—; R′ and R″ are eachindependently chosen from a hydrogen atom and C₁₋₄alkyl groups; n is aninteger from 0 to 6; and G is chosen from a hydrogen atom and C₁₋₄alkyl,aryl, heteroaryl, C₃₋₈cycloalkyl and saturated or unsaturatedheterocyclic groups, wherein the C₁₋₄alkyl, C₃₋₈cycloalkyl, aryl orheteroaryl groups are each independently unsubstituted or substitutedwith one or more substituents chosen from halogen atoms, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino, trifluoromethyl,trifluoromethoxy, carbamoyl, carboxy and cyano groups; and R² is chosenfrom a hydrogen atom, halogen atoms and C₁₋₄alkyl, C₂₋₅alkenyl,C₂₋₅alkynyl, C₁₋₄alkoxy, C₁₋₄alkylthio, mono or di-C₁₋₄alkylamino,C₁₋₄alkoxy-(CO)—, —NH₂, mono or di-C₁₋₄alkylamino-(CO)— and cyanogroups, wherein the C₁₋₄alkyl, C₂₋₅alkenyl and C₂₋₅alkynyl groups may beeach independently unsubstituted or substituted by one aryl orheteroaryl group; or b) R², R¹ and the —NH— group to which R¹ isattached, form a moiety chosen from the moiety of formulae (IIa) and(IIb):

wherein: each instance of R^(a) is independently chosen from a hydrogenatom, halogen atoms, —OH, —NH₂, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl,heteroaryl-C₁₋₄alkyl, saturated heterocyclic rings, C₁₋₄alkoxy, andC₁₋₄alkylthio groups; wherein the aryl or heteroaryl groups are eachindependently unsubstituted or substituted with at least one groupchosen from halogen atoms, C₁₋₄alkyl, C₁₋₄alkylthio, C₁₋₄alkoxy, mono ordi-C₁₋₄alkylamino, cyano, trifluoromethyl, trifluoromethoxy, carbamoyland carboxy groups; and R^(b) is chosen from a hydrogen atom, halogenatoms C₁₋₄alkyl, C₁₋₄alkylamino, aryl-C₁₋₄alkylamino and —NH₂ groups; ora pharmaceutically acceptable salt thereof, or a N-oxide thereof; withthe proviso that the compound is not chosen fromN-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide,N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-benzamideandN-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-yl-pyrazin-2-yl]-formamide;and (ii) at least one compound chosen from (1) antagonists of M3muscarinic receptors, (2) β2-agonists, (3) PDE4 inhibitors, (4)corticocosteroids, (5) leukotriene D4 antagonists, (6) inhibitors ofegfr-kinase, (7) p38 kinase inhibitors, (8) NK1 receptor agonists, (9)CRTh2 antagonists, (10) syk kinase inhibitors, (11) CCR3 antagonists and(12) VLA-4 antagonists, for simultaneous, separate or sequentialadministration.